Rome III Diagnostic Criteria for Functional Gallbladder and Sphincter of Oddi Disorders [8]
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He has done post-doctorates in China and South Korea (Institute of Modern Physics, CAS, China and Sungkyunkwan University, South Korea). His research interests include the fabrication of nanomaterials and their structural, magnetic, optical, and electrical characterizations. He has authored more than 90 articles and served as the editor of nine books. 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True biliary colic consists of episodes of steady pain across the right upper quadrant and epigastric regions, lasting from 30 minutes to 6 hours [1]. Such abdominal pain, when it lasts longer than 6 hours, is likely due to complications of gallstone disease such as acute cholecystitis or acute pancreatitis, or represents a non-biliary source of pain [1].
Classical biliary pain that occurs in the setting of gallstones represents symptomatic cholelithiasis. The symptoms associated with gallstones however are frequently confusing. In fact, only 13% of people with gallstones ever develop biliary pain when followed for 15–20 years [2], meaning that most (70-90%) patients with gallstones never experience biliary symptoms. Vague dyspeptic complaints like belching, bloating, flatulence, heartburn and nausea are not characteristic for biliary disease [3, 4]. Therefore, it is not surprising that cholecystectomy often fails to relieve such ambiguous symptoms in those with documented gallstones. In fact, cholecystectomy fails to relieve symptoms in 10-33% of patients with documented gallstones [5]. If the abdominal pain is misdiagnosed and instead due to functional gut disorders like irritable bowel syndrome, cholecystectomy would not provide a favorable outcome [4, 5, 6].
Biliary-type abdominal pain (also termed biliary colic) in the context of a structurally normal gallbladder has been referred to as “biliary dyspepsia”. True biliary pain manifests as steady, severe epigastric or right upper quadrant pain that might radiate through to the back and right infrascapular regions, lasting for at least thirty minutes but less than 6 hours. It can be associated with symptoms of nausea and vomiting, and may awaken the patient from sleep [8]. Episodes are recurrent but usually in a sporadic and quite erratic frequency. Its functional nature should be supported by an absence of markers of organic disease: normal liver and pancreatic biochemistries, and negative diagnostic imaging. No structural basis should be evident to explain the pain.
Functional biliary pain has also been termed:
Following removal of the gallbladder, biliary pain has been attributed to sphincter of Oddi dysfunction (SOD). SOD represents intermittent obstruction to the flow of biliopancreatic secretions through the sphincter of Oddi in the absence of biliary stones or a ductal stricture [11]. The Rome III Consensus has developed criteria for functional biliary-type pain (Table 1) [8].
Dyspepsia overall is a common symptom in the general population with reported prevalence rates ranging between 10-45% [12]. Such estimates are confounded by the use of differing criteria for defining dyspepsia as well as a recurrent failure to exclude patients who primarily report heartburn symptoms12. Nevertheless, dyspepsia remains a common issue with annual incidence rates estimated between 1-6%[13]. In the United States, there were 4,007,198 outpatient visits for gastroenteritis or dyspepsia and 130,744 hospital admissions for functional or motility disorders in 2009 [14]. This represents a 26% increase from the year 2000, which suggests an upsurge in the overall incidence of dyspepsia14.
The true prevalence of biliary dyspepsia is unknown. Estimates are generally based on the presence of non-specific clinical features and a lack of structural findings on ultrasonographic investigation of the biliary system. In large Italian population-based studies, 7.6% of men and 20.7% of women experienced biliary pain yet lacked gallstones on abdominal ultrasonography [15, 16].
With the advent of minimally invasive surgery, biliary dyskinesia has become a new indication for laparoscopic cholecystectomy increasing 348% in adults [17] and escalating 700% in pediatric patients over approximately a decade [18]. Large scale case series now list biliary dyskinesia as the primary indication for cholecystectomy in 10-20% of adults [17, 19-22] and 10-50% of pediatric patients [23-26].
In the US householder survey of presumably healthy adults, 69% expressed symptoms indicating a functional gastrointestinal syndrome within the previous three months and 1.5% had biliary dyspepsia following cholecystectomy [27]. Women were more commonly afflicted at 2.3% than men at 0.6% [27]. Nevertheless, sphincter of Oddi dysfunction (SOD) is uncommon in this population. SOD, when documented by ERCP manometry, occurs in less than 1% of the patients who have had their gallbladders removed and accounts for the abdominal pain in 14% of the patients with postcholecystectomy pain [28].
The biliary tract normally is a low-pressure conduit though which bile secreted from the liver reaches the duodenum. The gallbladder acts as a reservoir for decompression while storing bile in the interdigestive periods overnight and throughout the day [29]. Even in the digestive phase, gallbladder contraction does not elicit marked pressure spikes within the biliary tree because the sphincter of Oddi effectively relaxes. The hormone cholecystokinin (CCK) is primarily responsible for this reciprocity.
In the setting of cholelithiasis, biliary pain is assumed to originate from either an obstructive event (the gallbladder contracting on a closed cystic duct which is blocked by a gallstone) that increases intrabiliary pressure and/or inflammation (cholecystitis)10. Such obstruction also appears to stimulate the gallbladder mucosa to produce a phospholipase, which then hydrolyses fatty acids off lecithin to yield lysolecithin in bile. Lysolecithin, acting as a biological detergent, might then initiate an inflammatory reaction (cholecystitis). Subsequently, inflammatory mediators could trigger painful stimuli, while mechanoreceptor afferent fibers in the gallbladder and biliary tree conduct visceral pain information to the spinal cord and the brain. Thus, motor contraction, sensory afferents producing painful sensations and obstruction/inflammation may all play a role in the perception of acute biliary-type pain.
The basis for chronic functional biliary pain appears to reside in visceral hypersensitivity, altered central processing, and/or abnormal gastrointestinal motility. Prolonged or intense noxious stimuli, particularly when repeated, lead to sensitization of visceral nociceptors. These peripheral sensory neurons respond to potentially damaging stimuli by sending nerve signals to the spinal cord (dorsal horn) and then projecting centrally to the brain – the thalamus and cortex, the site of pain perception. Chronic irritation might then influence afferent input and the release of neuroactive chemicals in the dorsal horn of the spinal cord. Even when the peripheral irritation ceases, synaptic changes in the spinal cord can persist, causing "pain memory". Thus, irritation to the biliary tract can potentially sensitize the nervous system. In some, the central nervous system becomes so sensitive that
Acalculous biliary pain may represent a generalised motor disorder of the duct: the irritable gallbladder/sphincter of Oddi10. The abnormalities identified by impaired gallbladder emptying or increased tone in the sphincter of Oddi, for example, may reflect a more generalised motility disorder of the gut [32]. Moreover, biliary-type pain could originate from a neighbouring structure: for example, abnormal small intestinal motility. Gut smooth muscle in functional gut disorders exhibits altered sensitivity to regulatory peptides such as CCK, precipitating abdominal pain in some patients and confounding the interpretation of intestinal versus biliary pain.
Functional biliary disorders have been most prominently linked to abnormal motility of the gallbladder and/or sphincter of Oddi, in part because techniques exist to detect them in clinical practice. Biliary pain is construed to result in most instances from increased gallbladder pressure from either abnormal gallbladder contraction (“dyskinesia”) and/or structural or functional outlet obstruction either at the exit from the gallbladder (e.g.; abnormal cystic duct) or at the sphincter of Oddi (“the fighting gallbladder”). Reduced emptying and pain however may also reflect diminished gallbladder contractility (“hypokinesia”). Decreased gallbladder emptying has been attributed to abnormal CCK release, decreased gallbladder CCK receptor sensitivity or density, or increased cystic duct receptor sensitivity to CCK with impaired smooth-muscle contractility producing outlet obstruction [33].
Impaired gallbladder emptying, however, is also an important pathogenetic component in cholesterol gallstones. Cholesterol gallstone formation begins when the liver produces bile supersaturated with cholesterol, in excess of the solubilizing agents, bile salts and lecithin. In this first stage, the liver secretes excess cholesterol into bile canaliculi that is accompanied by lecithin as small, unilamellar vesicles. These fuse in this supersaturated bile to become cholesterol-rich, multilamellar vesicles (liquid crystals). Aided by nucleating factors (biliary proteins), cholesterol microcrystals precipitate out of solution. Mucin, a glycoprotein, secreted by the gallbladder mucosa, then acts as a matrix scaffold to retain these cholesterol microcrystals. Diminished gallbladder contractility facilitates retention, providing the residence time that is necessary for these microcrystals to agglomerate and grow into overt gallstones. Cholesterol constitutes the vast majority (>85%) of gallstones. A minority of gallstones are black pigment stones. These are composed of calcium bilirubinate polymers that result from abnormal bilirubin metabolism. Such black pigment stones tend to develop in advanced age, Crohn\'s disease, extensive ileal resection, cirrhosis, cystic fibrosis, and chronic hemolytic states [34].
Hence, a smooth muscle defect producing gallbladder hypomotility is intrinsic to cholesterol gallstone formation and disease [35, 36] and also occurs in chronic acalculous disease [37]. Both conditions yield biliary pain, creating a potentially confusing scenario. Evidence of microlithiasis in the gallbladder bile in some patients with biliary dyskinesia [38] may merely indicate that excessive cholesterol, likely a stage of stone formation in which macroscopic gallstones were not evident, compromised signal transduction in the gallbladder and was the mechanism for reduced emptying. Certainly any bile crystals or sludge may eventually result in calculous disease, causing obstruction of the gallbladder and symptoms of biliary pain, but this must be distinguished from functional gallbladder disease. The mechanism for chronic cholecystitis is unclear [39], while cholesterolosis with its accumulation of lipid products (triglycerides and cholesterol precursors and esters) is likely too common to have any clinical importance as a cause of biliary pain [38].
Gallbladder dysmotility is also associated with other conditions including functional gastrointestinal disorders, pregnancy, diabetes mellitus, obesity, cirrhosis [40], and the use of various medications (including atropine, morphine, octreotide, nifedipine, and progesterone) [41]. Interestingly, gut smooth muscle in the irritable bowel syndrome (IBS) also exhibits altered sensitivity to regulatory peptides such as CCK [42]. It is, therefore, not surprising that the gallbladder empties abnormally in some patients with IBS [43-45].
Although in sphincter of Oddi dysfunction, pain has classically been attributed to abnormal smooth muscle motility, there may also be a component of visceral hypersensitivity. Here, the hypersensitivity might arise in a structure adjacent to the sphincter, the duodenum [46, 47].
Despite biliary dyspepsia suggesting impaired digestion, there is no consistent relationship to eating. Historically, the abdominal discomfort and bloating that follow a heavy, fatty meal has been termed “fatty food” intolerance, connoting an association between fat content in the diet and biliary dyspepsia [48, 49, 59]. Patients with biliary dyspepsia may eat fewer meals, perhaps because their symptoms onset after eating [51]. In some, the sensation of fullness experienced relates to the amount of fat consumed. The presumed basis is fat releasing CCK and peptide YY, which are gut hormones important in regulating hunger and satiety. Patients with biliary dyspepsia, particularly those experiencing higher scores for nausea and pain, have higher concentrations of fasting and postprandial CCK compared to healthy individuals50. However, just as dyspepsia is not a particular manifestation of gallstone disease, fatty foods do not necessarily precipitate attacks of biliary colic [3, 52].
Structural causes affecting the gastrointestinal tract should be considered in any patient presenting with dyspepsia (Table 2) [12]. Gallstones, biliary sludge and microlithiasis must be eliminated [12]. As decreased gallbladder emptying is a key investigation leading to the diagnosis of a functional gallbladder disorder, other causes of impaired gallbladder emptying should be identified to obviate confounders (Table 3) [53].
\n\t\t\t\t | \n\t\t
1. Episodes lasting 30 minutes or longer 2. Recurrent symptoms occurring at different intervals (not daily) 3. The pain builds up to a steady level 4. The pain is moderate to severe enough to interrupt the patient’s daily activities or lead to an emergency department visit 5. The pain is not relieved by bowel movements 6. The pain is not relieved by postural change 7. The pain is not relieved by antacids 8. Exclusion of other structural disease that would explain the symptoms | \n\t\t
\n\t\t\t\t | \n\t\t
The pain may present with 1 or more of the following: 1. Pain is associated with nausea and vomiting 2. Pain radiates to the back and/or right infrasubscapular region 3. Pain awakens from sleep in the middle of the night | \n\t\t
Rome III Diagnostic Criteria for Functional Gallbladder and Sphincter of Oddi Disorders [8]
\n\t\t\t\t | \n\t\t||
\n\t\t\t | Gastroesophageal reflux disease Gastric or esophageal cancer Gastric infections Gastroparesis Inflammatory bowel disease Irritable bowel syndrome Peptic ulcer disease Food intolerances Drug intolerances | \n\t\t|
\n\t\t\t\t | \n\t\t||
\n\t\t\t | Cholelithiasis, choledocholithiasis Pancreatitis Pancreatic neoplasms | \n\t\t|
\n\t\t\t\t | \n\t\t||
\n\t\t\t | Adrenal insufficiency Diabetes mellitus Hyperparathyroidism Renal insufficiency Thyroid disease | \n\t\t
Organic Causes for Dyspepsia [12]
\n\t\t\t\t | \n\t\t|||||
\n\t\t\t | Cholesterol gallstones | \n\t\t||||
Prior to stone formation as evidenced by microcrystals of cholesterol and following medical dissolution | \n\t\t|||||
Pigment stones | \n\t\t|||||
\n\t\t\t | Hemoglobinopathies | \n\t\t||||
Cholecystitis | \n\t\t|||||
\n\t\t\t | Acute or chronic, with or without stones | \n\t\t||||
\n\t\t\t\t | \n\t\t|||||
\n\t\t\t | Obesity, diabetes, pregnancy, VIPoma, sickle hemoglobinopathy | \n\t\t||||
\n\t\t\t\t | \n\t\t|||||
\n\t\t\t | Myotonia dystrophic Denervation (spinal cord injury, vagotomy) | \n\t\t||||
\n\t\t\t\t | \n\t\t|||||
\n\t\t\t | Irritable bowel syndrome | \n\t\t||||
\n\t\t\t\t | \n\t\t|||||
\n\t\t\t | Celiac disease, fasting/TPN | \n\t\t||||
\n\t\t\t\t | \n\t\t|||||
\n\t\t\t | Anticholinergic agents, calcium channel blockers, opioids, ursodeoxycholic acid, octreotide, cholecystokinin-A receptor antagonist, nitric oxide donors, female sex hormones (progestins) | \n\t\t
Causes of Impaired Gallbladder Emptying [52]
The diagnosis of functional disorders of the gallbladder and sphincter of Oddi should be based on the Rome III criteria for functional gallbladder and sphincter of Oddi disorders (Table 1).
Preliminary investigations to rule out structural disease that might be the origin of the pain must include liver and pancreatic biochemistries and esophagogastroduodenoscopy. All should be normal in functional gallbladder disorder. The search for gallstones must be scrupulous. Transabdominal ultrasound is critical in being capable of detecting stones down to 3-5 mm in size. Endoscopic ultrasound (EUS) is more refined for microlithiasis: tiny stones < 3mm and biliary sludge [10]. Microscopic examination of gallbladder bile collected from the duodenum following IV CCK stimulation can detect deposits, either cholesterol as birefringent crystals (Figure 1) or pigment in the form of dark red-brown calcium bilirubinate. Both techniques are fairly specific (in the order of 90%). Detection of microlithiasis by EUS however is more sensitive (96% versus 67%) than microscopic bile examination [54, 55], and also more available in most centres. Regardless, the use of these investigations in biliary dyskinesia is limited by their invasive nature.
Cholesterol microcrystals in aspirated duodenal bile following CCK stimulation. The collected golden brown duodenal bile is first centrifuged and then examined under polarizing microscopy. As seen here, cholesterol is evident as birefringent, rhomboid-shaped crystals, characteristically with a notch in one corner.
Assessment of gallbladder emptying by cholecystokinin-cholescintigraphy is currently the key to diagnosing functional gallbladder disorder. The gallbladder ejection fraction (GBEF) is best measured via a nuclear medicine hepatobiliary scan. The radiopharmaceutical, technetium 99m-labelled iminodiacetic acid (HIDA), when infused intravenously, is readily taken up by hepatocytes, excreted into the bile, and accumulates in the gallbladder [37, 56, 57]. Infusion of the CCK analogue, Sincalide™ (the 8-amino acid C-terminal fragment of cholecystokinin, CCK-8), then initiates gallbladder evacuation (Figure 2). There has been a wide variation in methodology, leading to a consensus recommendation: Sincalide™ should be infused at 0.02μg/kg over 60 minutes. Normal gallbladder ejection fraction should be ≥ 38%, according to a recent consensus conference [58]. In selected cases of recurrent biliary pain in which no structural cause is evident, no stone disease is apparent and there exists no other associated cause for impaired gallbladder emptying, cholecystectomy is a reasonable consideration when the gallbladder ejection fraction is reduced at less than 35-40% [59].
A. Normal gallbladder emptying on CCK-cholescintigraphy. The gallbladder is visualized 30 minutes after the injection of the 99m-labelled technetium iminodiacetic acid radiopharmaceutical (HIDA scan). Cholecystokinin is then infused (shown as arrow). Prompt gallbladder emptying (70% here) then ensues with the radiolabel ejected into the small intestine. The gallbladder is depicted as GB, before and after the CCK infusion. [
There is as yet no predictive value for CCK-cholescintigraphy in those with established yet uncomplicated (‘silent”) gallstones. The influence of gallbladder evacuation on the development of biliary symptoms and on the severity of disease remains unclear [56]. The sluggish gallbladder does not protect an individual with stones from developing pain.
The use of a fatty meal to stimulate gallbladder contraction may be more physiological and cheaper than CCK but does not enjoy an established protocol with normal values. Another limitation is that endogenous CCK release depends upon gastric emptying of the meal; gastroparesis often accompanies functional gastrointestinal disorders [58].
Real-time ultrasound has also been used to measure volume changes as the gallbladder empties. Its advantage over a nuclear medicine scan obviates exposing the patient to ionizing radiation. Quantitative ultrasonography, based on geometric assumptions, however is operator-dependent, limiting its accuracy. Although 3-dimensional and 4-dimensional ultrasounds appear to correlate reasonably well with HIDA scans in identifying reduced gallbladder ejection fractions [60], CCK-cholescintigraphy is more precise and remains the standard [56, 58, 60].
The CCK-provocation test aimed to reproduce the biliary pain following an infusion of CCK, implicating the gallbladder as the culprit. This test has fallen out of favor due to lack of objectivity and specificity for biliary dyskinesia [42, 61]. Rapid infusion of CCK can elicit abdominal pain even in normal individuals [10].
The algorithm for diagnosing and managing functional gallbladder disorder is outlined in Figure 3 [8].
Algorithm for the diagnostic workup and management for biliary dyspepsia due to functional gallbladder disorder [
Sphincter of Oddi dysfunction implies that the basis is a motility disorder of the sphincter that intermittently results in pain, elevated liver and/or pancreatic enzymes, a dilated common duct and potentially pancreatitis. The Milwaukee classification originally categorizes SOD into three types, separating functional biliary and pancreatic sphincter of Oddi disorders on the basis of symptoms, laboratory tests and radiological imaging [8, 62-65] (Table 4). As these require an invasive procedure, endoscopic cholangiopancreatography (ERCP), to measure common duct size and biliary drainage, the criteria have been revised to use non-invasive imaging for estimating duct size of on an abdominal ultrasound [64].
\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t
Typical biliary type pain Liver enzymes (AST, ALT or ALP) > 2 times normal limit documented on at least 2 occasions during episodes of pain Dilated CBD > 8 mm in diameter Positive manometry for biliary SOD (seen in 65-95% of patients) | \n
\n\t\t | \n
Biliary type pain and one of the above criteria (laboratory or imaging) | \n
\n\t\t | \n
Biliary type pain only | \n
Pancreatic type SOD | \n
\n\t\t | \n
Pancreatic type pain Amylase and/or lipase > 2 times upper normal limit on at least 2 occasions during episodes of pain Dilated pancreatic duct (head > 6 mm, body > 5 mm) | \n
\n\t\t | \n
Pancreatic type pain, and one of the above criteria (laboratory or imaging) | \n
\n\t\t | \n
Pancreatic type pain only | \n
As in biliary dyspepsia due to gallbladder dysfunction, patients with suspected SOD should undergo evaluation with serum liver and pancreas biochemical tests, abdominal ultrasound, and esophagogastroduodenoscopy to rule out underlying structural disease as a cause for their abdominal symptoms. Consideration should also be given to magnetic resonance cholangiopancreatography (MRCP) to eliminate structural lesions such as stones, strictures and tumors. Dysfunction potentially might affect either or both segments of the sphincter of Oddi: biliary versus pancreatic sphincters or both (e.g.; occurring simultaneously).
Functional Biliary Sphincter of Oddi Disorder
Type I manifest biliary pain; abnormal liver biochemistries (elevated aminotransferases, alkaline phosphatase and/or bilirubin) >2 times normal on two or more occasions; plus a dilated common bile duct > 8mm on abdominal ultrasound. Most will exhibit biliary SO dysfunction on formal manometry. They are considered to have stenosis of the sphincter causing structural outflow obstruction.
Type II patients with biliary sphincter dysfunction experience the biliary-type pain plus exhibit one of either the laboratory or the imaging abnormalities.
Type III patients only complain of the pain. There are no laboratory or imaging abnormalities
Pancreatic-type SOD encompasses patients with pancreatic-type pain, elevated serum amylase or lipase plus pancreatic duct dilation.
Type I has pain, lipase elevation and pancreatic duct dilation
Type II has pain plus either lipase elevation or pancreatic duct dilation.
Type III has only pancreatic-type pain.
Investigations
ERCP Manometry.
The “gold” standard to diagnose SOD is sphincter of Oddi manometry. This entails endoscopic retrograde cholangiopancreatography (ERCP) allowing passage of a manometric catheter through the duct and measurement of basal sphincter pressures on slow withdrawal of the catheter. A basal sphincter pressure of greater than or equal to 40 mmHg is used to diagnose SOD [67]. Manometry is abnormal in 65-100% with type I, 50-65% with type II, and falls to 12-60% of biliary type III SOD patients [65, 67, 68]. Positive manometric findings, based on type, are similar in both types of sphincter dysfunction. The distinction between types I, II, and III SOD, however, is important as it may predict a favorable response to endoscopic sphincterotomy and thus, guide further management. The algorithm for diagnosing and treating functional biliary sphincter of Oddi dysfunction is outlined in Figure 4.
Algorithm for the diagnostic workup and management of sphincter of Oddi disorder (SOD) [
Non-invasive Methods
Additional non-invasive methods for diagnosing SOD have been studied, given the inherent risk of complications in sphincter of Oddi manometry, particularly precipitating pancreatitis, and the generally poor outcomes especially in patients with biliary type III SOD [69].
Ultrasonographic measurement of duct diameter
The common bile duct normally has a diameter of 6mm or less in healthy individuals whose gallbladders are intact. Above 8mm indicates biliary obstruction. This value becomes somewhat obscure following cholecystectomy, a situation in which dilation occurs to 10mm even in those without symptoms [70]. Adding a fatty meal to release CCK seeks to show duct dilation to indicate SO dysfunction but its diagnostic usefulness is limited.
Magnetic resonance pancreatography (MRCP)
Administration of the hormone secretin increases pancreatic exocrine secretion [71]. In suspected SOD involving the pancreas, secretin improves MRCP visualization of the pancreatic ducts to eliminate structural disease and elicits duct dilation [72]. Overall, secretin-stimulated magnetic resonance cholangiopancreatography (ss-MRCP) is not sensitive in predicting abnormal manometry results in patients with suspected SOD type III, though somewhat accurate in predicting results in patients with SOD type II (73%) [73].
Endosonography
Endoscopic ultrasound (EUS) generally has a low yield in diagnosing abnormalities in the context of a normal upper endoscopy and imaging studies in patients with SOD Type III [72, 74]. Only 8% of patients with suspected SOD Type III (normal endoscopy and standard imaging studies) have any pathology at EUS [74].
Hepatobiliary scintigraphy [10]
Nuclear medicine scanning of the biliary tract (choledochoscintigraphy) uses 99mTc HIDA as the radiopharmaceutical to measure biliary emptying: the transit time from the liver to the duodenum. Prolonged duodenal arrival reflects SO dysfunction [75]. Specificity approaches 90% but reported sensitivities are variable [76]. Although lacking controlled studies, choledochoscintigraphy is a reasonable non-invasive test before embarking on an intrusive approach with ERCP-manometry.
Morphine-prostigmine provocation (Nardi) test
The Nardi test assesses the response to an injection of morphine and prostigmine to provoke biliary sphincter spasm and stimulate pancreatic enzyme secretion. A positive test should elicit typical symptoms and/or increase in serum activities of pancreatic and/or liver enzymes. This provocative test is not specific or sensitive: 60% of normal individuals and others with IBS have a positive test [77]. Sphincterotomy decreases the pain and enzymatic response (amylase and lipase) to such provocation in only about 50% of individuals [78].
Functional Gallbladder Disorder
Medical
The medical options for management of functional biliary disorders are quite limited. The spice turmeric (Curcuma longa) modulates multiple cell signalling pathways and is a putative therapy for inflammatory bowel disease [79]. In patients with biliary dyspepsia, the extracts of Curcuma seem to reduce abdominal pain at least during the first week of treatment [80]. Oddly, curcumin increases gallbladder contraction. Tenoten, an anxiolytic, appeared to decrease the pain syndrome, burning and belching, and increase gallbladder contraction in a small Russian study assessing patients with biliary dyskinesia and personality disorders [81]. Such reports have marked limitations including small patient numbers and unclear diagnostic criteria for biliary dyspepsia. As such, further studies are needed to clarify any role for medical therapy in biliary dyskinesia, including use of agents like tricyclic antidepressants that help visceral hypersensitivity.
Surgical
Although there may be a rising tide of cholecystectomies being performed for biliary dyskinesia, most reports touting efficacy are retrospective reviews with small sample sizes and lack appropriate non-operative controls. One meta-analysis supported the notion of surgery in adults that provided 98% symptomatic relief compared to 32% with non-operative management [59]. Although the success rate in pediatric patients may reach 80% in some reports, a retrospective assessment of outcomes indicated no difference over a 2 year follow up: three-quarters of both the surgical and non-surgical groups improved [82]. Further, gallbladder emptying assessed by CCK-cholescintigraphy may not be a sensitive test that predicts a benefit from cholecystectomy [83]. Certainly cholecystectomy for dyspeptic complaints of gassiness, bloating, indigestion and fatty food intolerance is disappointing [84]. Despite the Rome III consensus [8], the literature does not yet support cholecystectomy being done routinely for biliary dyspepsia.
Functional Sphincter of Oddi Disorder
The aim in patients with SOD is to reduce the resistance caused by the sphincter of Oddi to the flow of bile and/or pancreatic juice [3]. This can be achieved by medical, endoscopic or surgical methods.
Medical
Medical management of sphincter of Oddi dysfunction is also unclear. Therapy has been primarily focused on the use of smooth muscle relaxants. Nifedipine, a calcium channel antagonist, has previously been studied with conflicting results in the treatment of sphincter of Oddi dysfunction. Nifedipine 20mg can significantly decrease the basal pressure in the sphincter of Oddi and also reduce the amplitude, duration and frequency of phasic contractions [85]. This effect is not seen at lower doses of nifedipine; unfortunately, hypotension is a common side effect at the higher dose. Nevertheless, nifedipine use over 3 months decreases pain, especially in patients with predominant antegrade propagation of phasic contractions [86]. Once treatment ceases, the effect becomes lost in a week [86]. Nicardipine also appears to have a similar effect on the sphincter of Oddi with a decrease in basal and phasic pressures following a single infusion [87].
Trimebutine (a spasmolytic), sublingual nitrates or a combination of both agents provides complete or partial relief of pain in most cases (64-71%) [88, 89]. All such studies however are limited by small patient numbers.
Several other medications such as anticholinergics (e.g.; hyoscine butylbromide), antispasmodics (e.g.; tiropramide), opioid antagonists (e.g.; naloxone), alpha-2 adrenergic agonists (e.g.; clonidine), and even corticosteroids may have a potential benefit in managing sphincter of Oddi dysfunction or functional gallbladder disorder [90]. Nevertheless, reports are limited in quality; well-done clinical trials are warranted.
Endoscopic Therapy
The goal of endoscopic therapy is to disable the dysfunctional sphincter through various methods. Botulinum toxin, a neurotoxin, when injected directly into the ampulla of Vater at endoscopy, improves symptoms in 44% of SOD patients for 6 to 12 weeks after the treatment [91]. Unfortunately, repeated injections of botulinum toxin may be associated with antibody formation and a subsequent reduced efficacy [90]. Hence, rather than being used to treat sphincter of Oddi dysfunction, botulinum toxin injections appear more helpful in directing further therapy, predicting the success of endoscopic sphincterotomy for pain relief [90, 91].
Endoscopic sphincterotomy (ES) is the current treatment for SOD Type I. At ERCP, deep cannulation of the bile (or pancreatic) duct allows electrocautery to sever the biliary or the pancreatic segment of the sphincter of Oddi. Pain relief after an ES is 90-95% in Type I patients, 85% in Type II patients with an abnormal sphincter of Oddi manometry and 55-60% in Type III patients with an abnormal manometry [92, 93]. Conversely, in patients with a normal manometry, the relief rates are much reduced: 35% for Type II and <20% in Type III patients, respectively [92, 93]. Complications from this procedure are mostly due to pancreatitis, which can be seen in up to 20% of patients [94]. ES as an indication of SOD results in a 2-5 fold increase in complications compared to the risk when performing this procedure for ductal stones [95, 96]. Placing a temporary stent in the pancreatic duct helps lessen such complications.
Surgical
Surgical options include transduodenal biliary sphincteroplasty with a transampullary septoplasty [97]. Due to the advances in endoscopic techniques, surgery is generally reserved for patients who experience restenosis or when endoscopy is not available [97]. Endoscopy is preferred with lower cost, morbidity and mortality compared to surgical procedures.
Functional gallbladder disease and sphincter of Oddi disorders can be quite frustrating for the patient as well as the physician, in terms of arriving at a diagnosis and effective therapeutic options. Initially, non-invasive investigations should be performed. Further, sphincter of Oddi manometry requires specialized endoscopic equipment as well as physician expertise. Unfortunately, this is not readily available in many centers. Perhaps with the procurement of these resources in the future, physicians may be able to predict which patients with SOD will benefit from endoscopic or surgical therapy. In terms of management, medical therapies should be tried as first line. Further, surgical and endoscopic management in type II and type III SOD should be initiated with caution. The suggested algorithm should assist the investigation and management of these patients (Figure 3 and 4).
Brain besides being a fascinating organ is also known for its complexity. From outside, this delicate organ is protected by a bony structure called skull while internally it is sheltered from noxious substances via some complex barrier systems. These protective barriers impede the treatment strategies adopted for therapeutic purposes [1]. The management of CNS disorders such as dementia, epilepsy, panic disorders, meningitis, and brain tumors greatly depends on the means of attaining higher drug levels at the targeted sites. Physico-chemical properties of the drug molecule mainly dictate its ability to penetrate these barriers and achieve a therapeutic outcome. Thus the ultimate pharmacological response obtained by the potential drug depends on multiple factors like its effectiveness, its uptake or penetration through protective barriers or its ability to bind with specific carrier proteins for efficient transport across the membrane [2]. Among these barriers, blood-brain barrier (BBB) presents one of the types that hinder the transport of the medicinal compounds for treating brain ailments. BBB serves as both physical and transport barrier and is present at the interface of blood and brain. It is a tight junction made of microvascular endothelial cells, astrocytes, and pericytes [3]. Therefore, the development of newer therapeutic strategies is the need of the hour to overcome these transport hurdles.
It is a tight physical junction present at the interface of CNS and blood circulation. It consists of endothelial cells that do not have fenestrations and thus restrict the influx of ions and other solutes into the brain from surrounding blood capillaries. Astrocytes and pericytes surround endothelial cells and thus make it almost an impermeable barrier. BBB allows paracellular transport of small lipophilic compounds (<400 Da) via passive diffusion. This barrier also offers active transport of some hydrophilic compounds by the means of transport proteins (e.g., P-glycoprotein) present at the junction. The transcellular pathway that is used by some compounds to enter the brain includes different mechanisms such as passive diffusion, specific transporters, and transcytosis [4].
Among the primary brain tumors, gliomas are considered the most common. These tumors make a barrier at their early stage termed as blood-brain tumor barrier (BBTB). Although BBTB is permeable at the core of glioblastomas, however, it closely resembles BBB at the peripheral regions. This combination of BBB and BBTB leads to an additional hindrance for drug delivery to reach the glioblastoma cells and thus requires newer drug development strategies to aid drug delivery to the tumor site [5].
Efflux pumps also serve as additional barriers in drug delivery to the brain that are present in endothelial cells lining. These efflux pumps are made up of protein complexes called adherens junctions primarily regulate the permeability of the endothelial barrier [6].
Blood-cerebrospinal fluid also acts as a barrier that limits the free movement of molecules and drug compounds across the brain by strictly regulating the transfer of solutes between the blood and CSF [7].
Mainly lipophilic drugs are used to treat CNS ailments and possess a molecular weight below 400 Da and log P between −0.5 and 6.0 [8, 9]. For drugs that are ionized at physiologic pH, it is their unionized fraction that determines the concentration gradient across the BBB for passive diffusion [2]. By considering these facts, a drug should be designed in such a manner that it has optimal lipid solubility so that it penetrates BBB and maintains a therapeutic concentration in the brain. But this is not that simple because only increasing the lipophilicity of the drug molecule via certain chemical modifications may not attain the desired pharmacokinetic effects as it may lead to decreased systemic solubility and bioavailability. It may also have increased protein binding and higher uptake by liver and reticuloendothelial system which ultimately leads to increased metabolism thus leading to diminished active drug concentration at the target site [2]. There are certain drug molecules that penetrate the BBB besides what their lipid solubility suggest. This penetration is attributed to the carrier-mediated transport of these polar compounds present at the tight junctions [10].
Brain targeting is potentially difficult because of multiple barriers. Recent advances in nanotechnology present opportunities to overcome such limitations and to deliver the drug to the brain targets. Nanopharmaceuticals are the relatively newer field that employed “therapeutic containing nanomaterial” with unique physicochemical properties due to their small size (one to several 100 nm), high surface to volume ratio and flexibility to alter their properties [11]. An alternate definition can be pharmaceuticals engineered on the nanoscale for the therapeutic purpose [12]. Nanopharmaceuticals comprised of different nanomaterial like polymers, lipids, amphiphilic material, metals, inorganic elements, carbon nanotubes, dendrimers, etc., to constitute nanocarriers which can be fabricated in different sizes, shapes, morphology, surface charges and surface groups for the brain-specific targeted delivery of the drug across barriers. Nanopharmaceuticals mediated drug delivery system has the power to penetrate drug moieties across CNS, either passively or actively, and improve bioavailability and therapeutic efficacy of the drug even at a lower concentration. Currently, available marketed nanopharmaceuticals for the brain are mentioned in Table 1.
Route | Brand | Nanocarrier | Indication | Manufacturer |
---|---|---|---|---|
SC | Copaxone | Glatiramer acetate | Multiple sclerosis | TEVA |
IV | DepoCyt® | Cytarabine encapsulated in multivesicular liposomes (20 μm) | Lymphomatous malignant meningitis | Leadiant Biosciences |
Epidural space injection | DepoDur® | Morphine sulfate encapsulated in multivesicular liposomes (17–23 μm) | Chronic pain | Pacira Pharmaceuticals |
IV | Opaxio® | Paclitaxel covalently linked to SLN | Glioblastoma | Cell Therapeutics |
Intratumoral Injection | NanoTherm® | Aminosilane-coated superparamagnetic iron oxide (15 nm) nanoparticles | Local ablation in glioblastoma, prostate, and pancreatic cancer | Magforce |
Oral | Avinza® | Morphine sulfate nanocrystals | Psychostimulant | Pfizer/King Pharma |
Oral | Focalin XR® | Dexmethylphenidate HCl nanocrystals | ADHD | Novartis |
Oral | Ritalin LA® | Methylphenidate HCl nanocrystals | ADHD | Novartis |
SC injection | Plegridy® | Polymer-protein conjugate (PEGylated IFN Beta-1a) | Multiple sclerosis | Biogen |
IM injection | Invega Sustenna® | Paliperidone | Schizophrenia | Janssen Pharms |
IV | AmBisome® | Amphotericin B liposome | Cryptococcal meningitis | Gilead Sciences, Inc. |
IV | Abelcet® | Amphotericin B liposome | Cryptococcal meningitis | Enzon Pharma |
IV | DaunoXome® | Daunorubicin liposome | Pediatric brain tumors | Under Phase I trial |
IV | Doxil®/Caelyx® | Doxorubicin HSPC, cholesterol, and DSPE-PEG2,000 | Glioblastoma and Pediatric brain tumors | Phase II Phase II |
IV | Myocet® | Doxorubicin EPC and cholesterol | Glioblastoma | Phase II |
IV | SGT-53 (SynerGene Therapeutics) | Cationic liposome with anti-transferrin antibody | Glioblastoma | Phase II |
— | Cornell Dots | Silica nanoparticles with a fluorophore, PEG-coated | Malignant brain tumors imaging | Phase I |
Marketed nanopharmaceuticals for brain disorders.
SC, subcutaneous; IM, intramuscular; IV, intravenous; AHDH, attention deficit hyperactivity disorder; IFN, interferon; DSPE, distearoylphosphatidylethanolamine; EPC, egg phosphatidylcholine; PEG, polyethylene glycol.
Nanopharmaceuticals could able to breach blood-brain barriers through various mechanisms. On the simple edge, their smaller size leads to passive delivery of the drugs through transcellular route across brain’s epithelial cells or choroid plexus. Criteria for the simple passive diffusion across the barriers are molecular size less than 400 Da, low hydrogen bonding capacity and lipophilicity [13, 14]. Therefore, lipophilic and tailored nanocarriers could deliver the drug through this mechanism.
While extremely hydrophobic molecules like nutrients (glucose and amino acids) pass through active diffusion mechanism with the aid of special transporter proteins. On the other hand, hydrophilic and larger molecules like transferrin and insulin pass through receptor-mediated transport across the membrane [15]. BBB majorly comprised of the endothelial layer which possessed tight junctions; the presence of proteins, namely occludins, claudins and adhesion molecules in the tight junction, make it a tougher barrier [16].
Nanopharmaceuticals are custom-made to surpass the brain barriers through these mechanisms:
Lipophilic nanocarriers (liposomes, solid lipid nanoparticles SLN) fuse with the endothelial cells and transport the drug through the transcellular pathway or endocytosis. Moreover, nanoparticles provide a sustained drug release pattern in the bloodstream, enabling higher drug concentration to cross BBB [17].
Furthermore, nanoparticles are functionalized with ligands or specific surfaces to trigger receptor-mediated transcytosis or carrier-mediated transport across BBB. Attachment of ligands like lactoferrin, transferrin, insulin facilitated receptor-mediated transport. Cationized ligands and peptides like albumin cross through receptor-mediated absorptive transport. Nanoparticles surface can be modified to utilize active transport system comprising P-glycoproteins, L-transporters, nucleoside transporter, ionic transporter, multidrug-resistant proteins that transfer the molecules into the brain by consuming adenosine triphosphate (ATP) [17]
Liposomes have been extensively studied and even FDA approved nanocarrier for brain disorders. Surface modulation of liposomes with functional proteins, peptides and polyethers aided targeted drug delivery for brain diseases [18]. PEGylated liposomes and glutathione-PEGylated liposomes evade body’s reticuloendothelial system and facilitate enhanced drug uptake across BBB [19]. Moreover, transferrin-modified liposomes [20], TAT peptide-conjugated liposomes [21], glucose-modified liposomes [22], and transferrin-folate bound liposome effectively deliver the drug across the barrier to treat multiple sclerosis [23]. Similarly, transferrin bound SLN and thiamine coated SLN were found to be efficacious in the treatment of cerebral malaria and increased drug uptake in the brain [24]. Mechanisms of transport across BBB are shown in Figure 1.
Different pathways for nanopharmaceuticals mediated transport across the blood-brain barrier (Under Creative Commons Attribution License 4.0,
Polymeric nanoparticles accumulate in the brain tissue by both passive and active mechanisms. Chitosan-poly lactic-co-glycolic acid (PLGA) nanoparticles showed enhanced delivery of coenzyme Q to the brain of transgenic mice through absorption mediated endocytosis [25]. In another study, PLGA was coupled with Tet-1 peptide to achieve neuronal targeting of curcumin in the treatment of Alzheimer’s disease. Retrograde transportation of curcumin across the barriers destroyed amyloid aggregates and scavenges oxidative radicals in the brain [26]. Similarly, ligand attached polymeric-lipidic nanoparticles like nerve growth factor (NGF) loaded poly butyl cyanoacrylate (PBCA) liposomes considerably deliver the drug across the BBB cholinergic system in the amnesic rodent model [27]. Likewise, inorganic nanocarriers show promising outcomes in terms of brain targeting. Amine functionalized multi-walled carbon nanotubes adopted transcytosis mechanism to pass BBB [28]. A natural substance wheat germ agglutinin-horseradish peroxide (WGA-hrp) was conjugated to gold nanoparticles (AuNPs) and administered in the IM injection into the mice. Results were remarkable in terms of drug penetration across BBB [29].
Dendrimers are the excellent drug carriers; their surface functionalization with folic acid, peptides, aptamers, amino acids, biotin, antibodies facilitated more site-specific targeting. To penetrate CNS barriers, dendrimers were conjugated with transferrin, lactoferrin, D-glucosamine, and leptin for more effective brain drug delivery [30].
Some other nanoparticulate systems like nanoemulsion and nanogel can be functionalized with targeting moieties (transferrin, insulin, peptides) for CNS drug delivery. Nanogels made up of PEG-polyethylenimine (PEI) and N-vinylpyrrolidone/isopropyl acrylamide have been tested to ensure CNS drug delivery potential [30].
BBB mediated drug uptake restrictions prompt scientists to investigate drug delivery potential of the nanopharmaceuticals to the brain through various routes. The ultimate objective was to enhance drug penetration across BBB and to reduce disease index. Up till now, the most commonly employed route was systemic administration through Intravenous (IV) injection. Other natural routes like oral, intranasal (IN), intrathecal (IT), intraperitoneal (IP) have been used as well. Some novel strategies like cerebral devices, implants, Ultrasound-guided nanoparticle delivery, osmotic delivery gain much attention in the recent era. Different nanopharmaceuticals are illustrated in Figure 2. List of all nanopharmaceuticals delivered through different routes have been mentioned in Table 2.
Nanopharmaceuticals classification on the basis of route and nanocarriers.
Route | Drug | Particle size | Nano component | Active ligand | Indication | References |
---|---|---|---|---|---|---|
Oral | Dalargin | ~100 nm | poly (butylcyanoacrylate) nanoparticle | Tween 80-PEG 20000 | Analgesic effect | [33] |
Oral | Indomethacin | ~320 nm | Lipidic core | poly (ε-caprolactone) coat | Glioblastoma treatment | [31] |
Oral | Saquinavir | 100–200 nm | polyunsaturated fatty acids (PUFA), Lipoid-80 and deoxycholic acid | Increase oral bioavailability and brain distribution | [32] | |
Oral | Estradiol | 138.8 ± 4.3 nm | polylactide-co-glycolide (PLGA) nanoparticles | Tween 80 coated | Alzheimer’s disease treatment | [34] |
Intraperitoneal (IP) | None | 220 ± 35 nm | Iron oxide (Fe3O4) nanoparticles | coated with a carbon shell derived from glucose | Brain cells localization | [36] |
Intranasal (IN) | Bromocriptine | 161.3 ± 4.7 nm | Chitosan nanoparticle | — | Parkinson’s disesase | [48] |
IN | Clonazepam | 15 ± 10 nm | Microemulsion | — | Increase brain/blood uptake ratio | [52] |
IN | Nimodipine | 30.3 ± 5.3 nm | Microemulsion | — | High brain uptake | [53] |
IN | Risperidone | 15.5 nm-nanoemulsion; 16.7 nm-mucoadhesive nanoemulsion | Nanoemulsion; mucoadhesive nanoemulsion | — | Schizophrenia treatment | [54] |
IN | Diadanosine-dideoxyinosine (dd) | 269–382 nm | Chitosan nanoparticles | — | Increase brain/plasm, CSF/plasma ratio | [12] |
IN | Rivastigmine | 143.1 to 3300 nm | Chitosan nanoparticle | — | Alzheimer’s disease | [50] |
IN | Venlafaxine | 167 ± 6.5 nm | Chitosan nanoparticles | — | Major depressive disorders and anxiety disorder | [51] |
IN | Duloxetine | 137.2 ± 2.88 nm | Nanostructured lipid carriers | — | Behaviorial improvement in major depressive disorder | [55] |
IN | Coumarin | 100 to 600 nm | methoxy-PEG-polycaprlactone | — | Enhanced brain penetration | [58] |
IN | Vasoactive intestinal peptide (VIP) | 90–100 nm | PEG-PLA nanoparticles (NP) | — | Protein translocation across BBB | [79] |
IN | Sumatriptan | 23.1 ± 0.4 nm | Miceller nanocarrier | — | Migraine therapy | [56] |
IN | Zolmitriptan | 23 nm | Miceller nanocarrier | Migraine therapy | [57] | |
IN | FITC labeled | 5 nm | AuNP | FITC | Brain specific delivery | [80] |
Intravenous (IV) | Azidothymidine | Transferrin anchored PEG nanoparticles | Viral infection | [81] | ||
IV | Valproic acid | Nanoparticles | Epilepsy | [82] | ||
IV | Tacrine | 35.58 ± 4.64 nm | PBCA NPs | Alzheimer’s disease | [83] | |
IV | Cabazitaxel | 24–68 nm | PEG modified Cellulose (Cellax) NPs | Glioblastoma | [84] | |
IV and intratumoral | Docetaxel/SiRNA | 110–150 nm | Peptide modified Cationic liposomes | Glioma | [85] | |
IV/Intranasal | Catalase | 9.5 nm | Exosomes | Parkinsonism | [86] | |
IV | HCFU | 50 nm | Nanogels | Glioma | [87] | |
IV (MRI) | Curcumin | <100 nm | Magnetic NPs | Detection of amyloid plexus in Alzheimer’s | [88] | |
IV | Sunitinib/anti-miR-21 oligonucleotide | <190 nm | NPs | Glioblastoma | [89] | |
IV | Monocolonal antibody (OX26) | 300–600 nm | PEG-chitosan NPs | Cerebral ischemia | [90] | |
Focused ultrasound+IV | FE3O4/SPAnH | — | Nanoparticles | Malignant glioma | [91] | |
Convection-enhanced delivery | CPT-11 | 96–101 nm | Liposomes | Intracranial tumor | [92] | |
Intrathecal | Fasudil | 100 nm | Liposomes | Subarachnoid hemorrhage | [93] | |
Intracranial | Paclitaxel | 3 mm | Nanoscale PLGA implants | Intracranial glioblastoma | [94] | |
Neural probes | Dexamethasone | 400–600 nm | PLGA nanoparticles in alginate hydrogel | Glial inflammation | [95] |
Nanopharmaceuticals administration through various routes.
PEG, polyethylene glycol; PLA, polylactic acid; FITC, fluorescein isothiocyanate; SPAnH, poly[aniline-c-sodium N-(1-one-butyric acid)] aniline; PBCA, poly(n-butyl cyanoacrylate); HCFU,
The oral route is the most convenient, non-invasive and compliant mode of administration. However, brain targeting through the oral route was not investigated largely mainly due to indirect systemic entry through absorption from the gastrointestinal tract (GIT). Harsh GIT environment, slow onset of action, shorter half-life, first pass elimination and reduced systemic absorption hampered drug therapeutic efficacy and bioavailability. Thus, oral drug delivery failed to deliver the therapeutic moiety to the brain efficiently. In this regard, nanopharmaceuticals must possess the properties to bear harsh enzymatic environment, overcome first pass metabolism and efficiently permeate through the intestinal epithelial barrier to reach the systemic circulation.
Scientists developed lipid nanocore surrounded by poly (e-caprolactone) and orally administered to the mice. The concentration of the loaded drug, indomethacin, was successively increased in the brain and efficiently treat glioblastoma in the mice model without causing BBB vessel alteration. This could serve as a basis for safe and effective brain targeting via oral route [31].
Similarly, orally administered saquinavir-loaded nanoemulsion significantly delivers the drug across BBB. Nanoemulsion was stabilized by deoxycholic acid which overpasses first-pass elimination of the drug. The oily phase, polyunsaturated fatty acids (PUFA) facilitates rapid transport to the brain. It laid the foundation for effective brain targeting through oral route [32].
Researchers formulated poly (butyl cyanoacrylate) nanoparticles, double coated with Tween 80 and polyethylene glycol (PEG)-2000 for the oral delivery of the dalargin to the brain. Dalargin is a hexapeptide, anti-nociceptive agent which could not cross BBB. However, its nanoformulation showed promising analgesic effects in the mice model, which demonstrated the potential of the nanoformulation for brain targeting via oral route [33].
Orally administered Tween 80 coated PLGA deliver estradiol successfully to the brain. The therapeutic efficacy in elevating Alzheimer’s disease was parallel to the nanoformulation administered intramuscularly [34]. In short, oral delivery of drug-loaded nanopharmaceuticals achieved preliminary success but still need to be further explored in the near future.
Intraperitoneal administration involved peritoneal cavity of the abdomen. The route is still under investigation. It has an advantage of delivering a larger amount of the drug and it is employed when a vein for the IV injection is not easily located. In addition, it can be employed when animals are not ready for oral administration. However, the route is currently limited to pre-clinical research in small animals and need to be scaled up [35].
Iron oxide nanoparticles were fabricated with the aim to target subcellular compartment of the brain cells. For this purpose, iron oxide nanoparticles with different shapes (round, biconcave, spindle, nanotube) were synthesized and coated with glucose derived fluorescent carbon layer. In-vivo administration through IP route indicated biconcave nanoparticles localized in the nuclei and nanotube-shaped nanoparticles located in the cytoplasm of the brain cells. While the carbon coated surface on iron oxide nanoparticles facilitated attachment of several therapeutic moieties on the nanoparticles for their delivery inside the brain cells [36]. Therefore, the IP route could serve as a major route to deliver the drug across the brain barriers.
Systemic route including IV drug delivery to the brain involves the receptor-mediated and adsorptive mediated transcytosis. It is the most exploited route of administration for the nanoparticles because of the immediate action systemically and locally by targeted delivery. Polybutyl cyanoacrylate (PBCA) was first used for the synthesis of the NPs intended for the brain. Analgesic dalargin was incorporated in the PBCA NPs with Polysorbate 80 coating and a marked level of analgesia was seen in the animal studies after IV administration of the NPs [37]. PBCA NPs with doxorubicin coated with Polysorbate 80 were studied for their brain delivery in the rats and showed the promising result in 2–4 hours as compared to the uncoated NPs after IV drug delivery [38]. In a similar study, Polysorbate 80 coated PBCA NPs with a size of 280 nm were evaluated for the delivery of Loperamide across BBB following IV injection. Results were quite promising in the
Recently, intranasal (IN) route for the drug delivery to the brain proved to be a reliable and non-invasive mode to cross BBB while possessing the ability to deliver a wide range of drug moieties like smaller molecules, larger macromolecules, growth factors, viral vectors and even stem cells to the brain. The transport involves either olfactory or trigeminal nerve which has a direct link from the brain and terminated in the nasal cavity at respiratory epithelium or olfactory neuroepithelium [47]. The nasal mucosa is the target tissue for the drug administration and possessed features like a larger surface area, porous endothelial membrane, huge blood flow, the absence of first-pass elimination and readily accessible. Olfactory region of nasal mucosa provide nose to brain targeting feature and could able to treat various CNS disorders like depression, pain, Alzheimer’s disease, glioblastoma, multiple sclerosis etc. Several dosage forms, sprays, suspensions, nebulizers, aerosols, gel, solutions can be utilized for IN drug delivery [47]. On the other hand, barriers like mucociliary clearance from nasal mucosa, enzymatic degradation and low degree of permeability across nasal epithelium hinder the drug targeting efficiency to the brain. As a solution, nanopharmaceuticals were used which overcome the clearance and other nasal problems due to their unique nature.
One of the studies demonstrated IN administration of chitosan nanoparticle to deliver bromocriptine, a dopaminergic agonist, to minimize motor function disorder associated with prolonged levodopa usage in the Parkinson’s disease. Results were promising in terms of motor function [48]. Didanosine-dideoxyinosine (ddI) is an antiretroviral therapy (HAART) and available in oral dosage forms, however, faced extensive degradation and elimination in GIT which decreases its bioavailability. To overcome the issues, dd loaded chitosan nanoparticles were administered through IN route. Results indicated higher brain to plasma, CSF to plasma and olfactory blood to plasma ratios in the case of IN delivered dd nanoparticles. It shows that nanoformulation can be directly delivered to the brain compartment through IN route [49].
Another research group fabricated rivastigmine loaded chitosan nanoparticle for inhibiting acetylcholinesterase in the brain through IN administration. The free drug had severe bioavailability issues and distributed to the non-targeted site with severe side effects when administered through oral or IV route. Here, chitosan nanocarrier and administration through nasal route enhanced brain uptake with higher brain/blood ratio. It further highlighted the role of nanocarrier and route in brain targeting [50]. Similarly, Venlafaxine (VLF) chitosan nanoparticles were administered to the brain through the nasal route for the treatment of major depressive disorders and anxiety disorder with improved brain uptake and enhanced bioavailability [51].
Another study showed microemulsion and mucoadhesive delivering clonazepam, an anxiolytic, sedative, hypnotic, anticonvulsant drug to the brain. The brain/blood uptake ratio of the intranasal microemulsion and mucoadhesive microemulsion were significantly higher than the IV administered microemulsion, indicating the effectiveness of IN route for brain-specific drug delivery [52]. Similarly, the microemulsion was used for the IN delivery of nimodipine to the brain cells. The microemulsion leads to 3-fold more drug uptake by the olfactory bulb than the IV route. AUC ratio of brain to plasma and cerebrospinal fluid (CSF) to plasma were higher after IN administration in comparison to IV injection. Thus, it could be a promising approach to treat neurodegenerative disorders [53]. Risperidone nanoemulsion and mucoadhesive nanoemulsion were administered through IN route for the treatment of schizophrenia. The composition of nanoemulsion included glyceryl monocaprylate as an oily phase, tween 80 as a surfactant and mixture of propylene glycol and transcutol as a co-surfactant. While mucoadhesive microemulsion had chitosan polymer which induces mucoadhesive properties. The nanoemulsion and mucoadhesive nanoemulsion improved risperidone bioavailability, prevent first pass metabolism and bypass BBB to achieve desired drug concentration at the targeted site. The brain/blood uptake ratio and drug transport efficiency were found to be significantly higher through nasal administration in comparison to the IV injection [54].
Furthermore, nanostructured lipid carriers comprising duloxetine was prepared and delivered to the brain via IN route for the treatment of the major depressive disorder. The results revealed prolonged drug release and therapeutic effect as demonstrated from improved behavior analysis after 24 hours [55].
Furthermore, micellar nanocarrier (amphiphilic nanocarriers) of sumatriptan was developed to treat an acute migraine to improve cerebral blood flow. Limitations of the drug associated with oral dosage forms and subcutaneous administration like poor bioavailability, shorter plasma half-life, and hepatic elimination have been resolved to much extent through incorporation in micellar nanocarrier. And increased brain concentration of the drug and site-retention can be achieved via nose to brain drug delivery [56]. Similarly, zolmitriptan-loaded micellar nanocarriers were prepared to target brain serotonin receptors and inhibit cranial vessel inflammation. Micellar nanocarriers were administered through nasal route with enhanced characteristics like lower particle size, higher permeation across nasal mucosa, appropriate flow rate, ability to load hydrophilic as well as hydrophobic drugs, enhanced site-retention and ultimately enhanced drug therapeutic activity [57].
Another polymer methoxy-PEG-polycaprolactone was used to encapsulate coumarin with promising brain penetration and myelin binding properties, while administered through nasal route [58]. Bioadhesive nanocarriers reported in the above studies overcome many hurdles associated with a nasal route like protection of drug against enzymatic degradation, enhanced permeability, and avoidance of mucociliary clearance. However, IN delivery of nanopharmaceuticals should be further improved with targeting moieties and incorporation of cost-effective approach.
Potential brain barriers can be by-passed by injecting the drug directly into the tissues using catheter. Such a direct delivery of therapeutic agent to the target site is termed as conventional enhanced delivery (CED). Many pre-clinical studies adapted CED to infuse nano-formulations directly into the brain [59]. C57BL/6 J mice were used to infuse a 10 μL solution of lipid nanocapsules (LNCs) having an average size of 70 nm into their skull at an infusion rate of 0.5 μL/min [60]. An alternate method for direct infusion was also reported in which drug-loaded micelles were injected by making small incisions on the skull. A foremost shortcoming CED technique is its invasiveness which requires high anesthetic doses prior to incisions, which resulted in the death of the experimental rats [61]. This technique also requires the optimization of certain factors like pH and osmolarity to surpass any brain damage [62].
Administering the drug into the carotid artery provides an alternative solution to direct delivery. This direct systemic delivery requires a catheter to directly inject drugs into the bloodstream. In a study, the efficacy of direct systemic delivery was reported almost twice to that of CED in terms of brain damage [63]. IV route is also used to deliver the drug directly into systemic circulation. Ferrociphenol-loaded lipid nanoparticles were infused to manage glioma via the IV route. The outcomes showed that mean survival of the rats was 28 days while mean survival rate recorded foe CED was of 24 days [62, 64].
Polylactic acid (PLA) and poly-dimethylaminoethyl methacrylate (PDMAEMA) were used to synthesize amphiphilic star-branched co-polymeric nanoparticles for intratumor delivery of the drugs for treating brain tumors. In a study, this system was used to deliver combined DOX and miR-21 inhibitor (miR-21i) into LN229 glioma cells directly. These micelles protected miR-21i from lysosome degradation and the release of DOX to the nucleus, which ultimately decreased the miR-21 expression. This combined DOX and miR-21i delivery surprisingly displayed an anti-proliferative efficiency compared with separate treatment of DOX or the miR-21. The outcomes revealed that this co-polymeric system was a better option for delivering genes and hydrophobic therapeutic agents [65].
Delivering the drug directly into the brain is another way of treating brain disorders. This local drug delivery has been approved by the US FDA [66]. Intrathecal administration of nanopharmaceuticals delivers the nano-drugs in the CSF. However, this route of administration is most commonly used for anesthetics and neurotic pain [67]. This route is under experimental phases in humans. It includes two different ways of delivering the therapeutic moiety, either by infusion in the intralumbar region or intraventricularly using an Ommaya reservoir placed subcutaneously and connected to the brain with a catheter [68]. Thioflavin-T was delivered by intrahippocampal injection for targeting the β amyloid in the brain using the nanoparticles. The data reported localization of thioflavin-T in the intracellular and extracellular spaces of the brain, which prevented the formation of β-amyloid aggregates in the Alzheimer’s disease. This same method can be adapted to deliver the anticancerous drugs as well as other analgesic peptides [69]. In an
Ultrasound facilitated drug penetration through brain barriers is yet another option for safe and reversible targeted drug delivery [72]. In this technique, ultrasound radiations are employed to generate shear stress on the vascular endothelium for a transient and reversible perforation in the BBB which facilitates the nanoscaled drug delivery to the targeted site. It appeared in a research outcome that docosahexaenoic acid binding with low-density lipoprotein NPs can penetrate the BBB by the application of ultrasound sonication. A near IR fluorescent dye examination revealed about 60 times greater accumulation of sonication facilitated drug delivery to the targeted site. The main advantage reported was lack of cytotoxicity or neuronal damage due to pointed ultrasound irradiation [73]. PEGylated PLA nanoparticles delivery to the brain was facilitated via ultrasound-induced perforation. β-specific antibody 6E10 was conjugated on PEG-PLA along with the coumarin 6 and DiR as fluorescent probes to assess the target site accumulation. Ultrasonication facilitated NPs penetration was about 2.5-fold more than the complementary non-sonicating therapy [74]. Ultrasound techniques can be used to aid the enhanced delivery of PEG-b-poly(l-Lysine) coupled with siRNA into glioma cells by 10-fold in conjunction with a newer gas-cored nanobubble [75].
Another targeted approach to the brain for delivering drugs is through the ocular route. The ocular route has so many advantages like reduced peripheral toxicity and direct delivery of therapeutic moiety in the target site [76]. Ocular and intranasal drug delivery for the brain was compared by a group, in which nerve growth factor (NGF) was used for treating Alzheimer’s disease. However, it was found out that intranasal drug administration was more effective and potent for brain disorders and ocular route did not perform well. However, many scientists are working for making the ocular route a success because of it being the compliant and non-invasive route [77]. There has been a huge room for the administration of nanocarrier through ocular route to the brain. Nanocarrier can facilitate drug delivery to the brain because of their size, site-retention properties and enhanced adhesion to the lacrimal fluid. The route can be exploited for the delivery of drugs and genes to CNS by avoiding systemic exposure via nanopharmaceuticals [78].
Brain-targeted drug delivery is a difficult matter due to anatomic and pathophysiological brain barriers. The current advances in nanotechnology provide a solution in the form of nanopharmaceuticals, drug containing nanocarriers, to cross the CNS barriers and to target the brain tissue in various disorders. Nanopharmaceuticals’ mode of administration into the body is an important aspect, which ultimately effects drug concentration in the brain and drug therapeutic effect. Current chapter highlighted the routes of administration through which nanopharmaceuticals can be delivered to reach the brain. Every route has pros and cons, nanopharmaceuticals overcome the route associated limitations in the delivery of drug to the brain due to their peculiar physicochemical properties and surface modulation. Translation this research area into the clinic still require investigations, as safety is the foremost concern and distribution to other body organs must be eradicated. Moreover, there is a need to control the drug delivery rate when nanopharmaceuticals reach the brain for safer action.
The authors declared no conflict of interest.
IntechOpen - where academia and industry create content with global impact
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\\n\\nSara Uhac, COO
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\n\nDr Alex Lazinica
\n\nAlex Lazinica is co-founder and Board member of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his Ph.D. in Robotics at the Vienna University of Technology. There, he worked as a robotics researcher with the university's Intelligent Manufacturing Systems Group, as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and, most importantly, co-founded and built the International Journal of Advanced Robotic Systems, the world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career since it proved to be the pathway to the foundation of IntechOpen with its focus on addressing academic researchers’ needs. Alex personifies many of IntechOpen´s key values, including the commitment to developing mutual trust, openness, and a spirit of entrepreneurialism. Today, his focus is on defining the growth and development strategy for the company.
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