What assessments are currently used to investigate and diagnose cerebral visual impairment (CVI) in children? A systematic review.

PURPOSE: Cerebral visual impairment (CVI) is the leading cause of childhood visual impairment in the developed world. Despite this, there are no agreed clinical guidelines for the investigation and diagnosis of the condition. Before development of such guidelines can commence, it is important to recognise which approaches are currently employed. This systematic review evaluated the literature to identify which methods of assessment are currently used to investigate and diagnose childhood CVI. METHODS: Medline, Embase, CINAHL, Scopus and the Cochrane Library databases were systematically searched in January 2020 using defined search terms. Articles were included if they: (i) were research papers, conference abstracts or research protocols published in peer-reviewed scientific journals, or relevant textbooks; (ii) included a clinical investigation of CVI in children; (iii) provided an explanation or criteria to diagnose CVI and (iv) were specifically investigating cerebral/cortical visual impairment. Methods used to a) assess and b) diagnose CVI were extracted from included articles. 'Assessment scores' were assigned for each method employed by researchers to investigate and diagnose CVI to quantify and compare approaches between articles. A quality grading was also applied to each article. RESULTS: Of 6454 identified articles, 45 met the inclusion criteria. From these, 10 categories of assessment utilised within included articles were identified: (1) Medical history, (2) Vision assessment/ophthalmologic examination, (3) Neuroimaging, (4) Visual behaviour and direct observation, (5) Structured history-taking, (6) Visual perception tests, (7) Ocular movement and posture assessment, (8) Intelligence/IQ assessment, (9) Clinical electrophysiology and (10) Neurodevelopmental tests. In terms of diagnostic criteria, the most commonly reported approach was one of exclusion, i.e., CVI was diagnosed when visual dysfunction could not be attributed to abnormalities detected in the anterior visual pathway. CONCLUSION: There is a lack of common practice in the approaches used by clinicians to investigate and diagnose CVI in children. At present, a 'diagnosis of exclusion' remains the most common means to diagnose CVI. Development of clinical guidelines for assessment and diagnosis are necessary to ensure consistency in the diagnosis of CVI and the timely implementation of support to alleviate the impact of CVI on the child's daily living.

Parents and teachers of children in special education settings value in-school eyecare and written reports of visual status.

OBJECTIVES: To evaluate parent and teacher opinion of the provision of in-school eyecare and jargon-free written reporting of visual status for children in special educational settings. PARTICIPANTS AND METHODS: A nationally-agreed, in-school eyecare framework for children attending special schools which recommends a full eye examination, dispensing of spectacles and provision of a jargon-free written report of visual outcomes to parents and teachers, was provided to 200 children (mean age 10 years, 9 months; 70% male) attending a special school in the UK. The written 'Vision Report' detailed, in lay-language, results from the eye examination and provided practical advice to alleviate the impact of vision difficulties both at home and in the classroom. Following implementation of the framework, parents and teachers completed a feedback questionnaire to determine their opinion of the in-school eye examination and utility of the Vision Report. RESULTS: Parents of 123 participants returned a feedback questionnaire. Eighty-eight participants were represented by the 23 teachers who returned a questionnaire. The in-school eyecare was rated positively for children in special education by 82.4% of parents and 80.9% of teachers. Key benefits included the familiarity of the in-school setting (81.3% of parents and 100% of teachers agree), the convenience of the setting for parents (74.0% of parents and 100% of teachers agree), and the opportunity for teachers to speak directly to eyecare providers regarding a child's visual needs (82.6% of teachers agree). The information provided by the Vision Report was deemed useful day-to-day by 78.3% of parents and 100% of teachers. The majority (80%) of teachers implemented classroom modifications suggested in the report, whereas only 47.9% of parents reported implementation of modifications at home. CONCLUSIONS: Provision of in-school eyecare is valued by parents and teachers of children in special education settings. Jargon-free, written reports of visual status are valued and utilised by parents and teachers. Further support is required to aid parents in implementing vision modifications at home.

Decoupling the role of image size and calorie intake on gastric retention of swelling-based gastric retentive formulations: pre-screening in the dog model.

Gastric retention is postulated as an approach to improve bioavailability of compounds with narrow absorption windows. To elucidate the role of image size on gastric retention and pharmacokinetics, formulations with different image sizes and swelling kinetics but similar dissolution rates were designed and imaged in dogs. Diet had a clear effect, with increasing calorific intake prolonging retention in the dog model. In contrast to clinical observations, no obvious effect of image size on gastric retention was observed in the dog, with the larger gastric retentive (GR) and smaller controlled release (CR) formulations both demonstrating similar gastric emptying. Comparable pharmacokinetic profiles were observed for the two formulations, corroborating the imaging data and providing evidence of similar in vivo dissolution rates and dosage form integrity in the dog. Food, specifically meal composition, resulted in comparable enhancements in exposure in the dog and clinic due to prolonged gastric retention. However, differentiating retention based on image size in the dog was not feasible due to the smaller pyloric aperture compared to humans. This work illustrates that the dog is capable of determining the pharmacokinetic advantage of gastric retention relative to immediate release (IR) or CR formulations, however, has limited value in differentiating between CR and GR formulations.

Assessment of gastrointestinal pH, fluid and lymphoid tissue in the guinea pig, rabbit and pig, and implications for their use in drug development.

Laboratory animals are often used in drug delivery and research. However, basic information about their gastrointestinal pH, fluid volume, and lymphoid tissue is not completely known. We have investigated these post-mortem in healthy guinea pigs, rabbits and pigs, to assess their suitability for pre-clinical studies by comparing the results with reported human literature. The mean gastric pH (fed ad libitum) was 2.9 and 4.4 in guinea pig and pig, respectively. In contrast, a very low pH (1.6) was recorded in the rabbits. The small intestinal pH was found in the range of 6.4-7.4 in the guinea pigs and rabbits, whereas lower pH (6.1-6.7) was recorded in the pig, which may have consequences for ionisable or pH responsive systems when tested in pig. A relatively lower pH than in the small intestine was found in the caecum (6.0-6.4) and colon (6.1-6.6) of the guinea pig, rabbit and the pig. The water content in the gastrointestinal tract of guinea pig, rabbit and pig was 51g, 153g and 1546g, respectively. When normalized to the body weight, the guinea pig, had larger amounts of water compared to the rabbit and the pig (guinea pig>rabbit>pig); in contrast, a reverse order was found when normalized to per unit length of the gut (guinea pig

An observational study on the influence of solvent composition on the architecture of drug-layered pellets.

Pelletization for the manufacture of modified release multiparticulate drug delivery systems is often considered to be well defined and robust. However, small differences in formulation conditions can lead to surprising changes to the expected outcomes. We observed that extended release tramadol hydrochloride pellets, prepared by solution layering an ethanolic solution of drug on a non-pareil, resulted in highly unusual pellet architecture with deep indentations which prevented the application of a homogeneous outer coating of ethylcellulose and talc, and negatively influenced the desired modified release characteristics. Modification of outer coating thickness and process temperature showed no improvement in release characteristics. A solution to the problem was found in the incorporation of 10% v/v water into the ethanolic drug layering solution, resulting in the production of drug-loaded pellets with a smooth morphology which allowed the application of a coherent outer coating able to retard drug release. The surprising difference in pellet morphology between the two solvent drug layering systems may be attributed to differences in solvent evaporation rates. This demonstrates that established techniques are sometimes less straightforward than thought as small changes in formulation have significant effects on the resulting product in a way which is not always well understood.

Colonic treatments and targets: issues and opportunities.

The colon provides a plethora of therapeutic opportunities. There are multiple disease targets, drug molecules, and colon-specific delivery systems to be explored. Clinical studies highlight the potential for systemic delivery via the colon, and the emerging data on the levels of cell membrane transporters and metabolic enzymes along the gut could prove advantageous for this. Often efflux transporters and metabolic enzyme levels are lower in the colon, suggesting a potential for improved bioavailability of drug substrates at this site. The locoregional distribution of multiple metabolic enzymes (including cytochromes), efflux transporters (including P-glycoprotein and breast cancer resistance proteins), and influx transporters (including the solute carrier family) along the intestine is summarized. Local delivery to the colonic mucosa remains a valuable therapeutic option. New therapies that target inflammatory mediators could improve the treatment of inflammatory bowel disease, and old and new anticancer molecules could, when delivered topically, prove to be beneficial adjuncts to the current systemic or surgical treatments. New issues such as pharmacogenomics, chronotherapeutics, and the delivery of prebiotics and probiotics are also discussed in this review. Targeting drugs to the colon utilizes various strategies, each with their advantages and flaws. The most promising systems are considered in the light of the physiological data which influence their in vivo behavior.

Drug distribution in enteric microparticles.

The aim of this study was to assess the distribution of three fluorescent drug or drug-like molecules in enteric microparticles. Microparticles were prepared using the pH-responsive methylmethacrylate polymer Eudragit L by an emulsion solvent evaporation process. In the process drug and polymer are dissolved in ethanol, and dispersed in a liquid paraffin external phase using sorbitan sesquioleate as stabiliser. The incorporation and distribution of riboflavin, dipyridamole and acridine orange into these microparticles were investigated using confocal laser scanning microscopy (CLSM). The influence of the physicochemical properties of the molecules (solubility in the inner phase, partition coefficient [ethanol/paraffin]) on the distribution, encapsulation efficiency and pH-responsive dissolution behaviour of the microparticles were examined. The drug that tended to partition in ethanol rather than liquid paraffin (riboflavin) was efficiently encapsulated and evenly distributed. In contrast, compounds which partitioned in favour of the liquid paraffin localised towards the surface of the microparticles and exhibited lower encapsulation efficiency (dipyridamole and acridine orange). All three sets of drug-loaded microparticles showed a limited release in acid (<10% release); drug distribution appeared to have a minimum effect on drug release. This microparticle technology has the potential to provide effective enteric drug release with a wide variety of molecules.

Meal-induced acceleration of tablet transit through the human small intestine.

PURPOSE: The transit of dosage forms through the small intestine is considered to be constant at around 3 h, and unaffected by the presence of food. Here we address this assumption and examine how the timing of tablet and food administration can influence small intestine transit time. METHODS: A non-disintegrating, radiolabelled tablet was given to ten healthy volunteers in a three-way crossover study using three different feeding regimens (1) fasted (tablet administered on an empty stomach and food withheld for four hours) (2) fed (tablet administered after food) and (3) pre-feed (tablet administered 45 min before food). Tablet transit through the gastrointestinal tract was followed using gamma scintigraphy. RESULTS: The small intestinal transit times of tablets after fasted and fed dosing regimens were similar, median 204 and 210 min respectively. With the pre-feed dose, small intestinal transit time was significantly shorter than in the fasted or fed state at 141 min. With this dosing regimen, in six of the volunteers tablets were in the upper small intestine when food arrived and these had a median small intestinal transit time of 100 min. CONCLUSIONS: The timing of food ingestion has a clear effect on small intestinal transit of single-unit formulations and this has implications for drug bioavailability.

Microbiota-triggered colonic delivery: robustness of the polysaccharide approach in the fed state in man.

Polysaccharide-based colonic drug delivery requires that the polysaccharide in question avoids pancreatic digestion but undergoes fermentation by the colonic bacteria. Resistance of such dosage forms to pancreatic enzyme digestion is generally only tested in the fasted state, despite the higher enzymatic challenge in the fed state. Theophylline pellets coated with a polysaccharide-based (amylose) colon-specific film were administered to seven healthy volunteers (two-way crossover study, fed/fasted). The transit of the pellets through the gut was followed by gamma scintigraphy. The amount of drug released in the gut from the theophylline pellets was calculated after recovering and assaying any intact pellets in the faecal material. Of the drug released, the amount absorbed was measured using plasma profiling. Gastric empyting of pellets was delayed in the fed state, and this translated to a delayed colon arrival time. In both fed and fasted states, there was no drug release in the stomach or small intestine confirming the ability of the amylose in the coating to resist pancreatic digestion despite elevated enzyme levels in the fed state. Drug plasma levels were detected after the pellets arrived in the colon and there was a delayed T(max) in the fed state; the mean caecal arrival time in the fasted state was 5.5 +/- 1.1 h and the T(max) was 9.3 +/- 0.5 h, whereas in the fed state the mean caecal arrival time was 6.9 +/- 2.1 h and the T(max) was 10.3 +/- 0.8 h. On average, over 92% of the drug was released in the colon; the remaining was removed in faecal material. Bioavailability was similar (p>0.05) in both feeding states (26.0 +/- 6.4 microg h/ml fasted and 24.4 +/- 5.1 microg h/ml fed). In conclusion, feeding has no detrimental effects on the behaviour of this polysaccharide-based colonic delivery concept.

An in vivo comparison of intestinal pH and bacteria as physiological trigger mechanisms for colonic targeting in man.

Targeting the colon for site-specific oral delivery can exploit one of two main physiological triggers; the intestinal pH changes or the increase in bacterial numbers in the distal gut. This study aimed to assess how these triggers compared in vivo to determine which concept provides better colon-specific release. Pellets were prepared using theophylline (model drug) and coated with methacrylic acid/methylmethcrylate co-polymer (Eudragit S [a pH-responsive polymer which dissolves above pH 7]) or amylose/ethylcellulose (a polysaccharide/polymeric mixture which is partially digested by colonic bacteria). The immediate release (uncoated) and the two sets of modified release (coated) pellets were administered to eight healthy fasted volunteers in a three-way crossover study. Drug levels were measured in the plasma, and the transit of the modified release pellets was followed by gamma scintigraphy. The immediate release pellets had T(max) values ranging from 0.5-2 h and bioavailability (AUC) ranging from 24.8-50.7 mcg h/ml. The pH-responsive pellets released drug in seven out of eight subjects. In those subjects in whom drug release occurred, the pellets had variable in vivo performance (T(max) ranging from 5-9 h; AUC 8.8-55.0 mcg h/ml) and drug release started in the small intestine for these pellets. The bacterially-triggered pellets (T(max) 8-10 h; AUC 16.5-47.9 mcg h/ml) were colon-specific; drug was detected in the blood only when the pellets reached the colon and release was more sustained than the pH system. The use of the bacterially-triggered delivery concept provided improved colonic delivery over the pH approach.

Gut instincts: explorations in intestinal physiology and drug delivery.

We need to look beyond our gut instincts to use information on "simple" intestinal physiological parameters as they have been presented to us in the past. Here we present a discussion on such parameters, old and new, and ask how much we really understand them. Behaviour of drugs and delivery systems in the intestine depends on many physiological factors including fluid volume, fluid composition, transit, motility, bacteria and pH, which are further influenced by food, gender and age. These are often considered well understood, but their true variability and idiosyncrasies are not fully appreciated or utilised in intestinal dosage form design or in vitro testing. There are still many unknowns in these areas. The distal gut especially has been neglected, and the influence of disease is often ignored. As pharmaceutics moves forward into the molecular era an understanding of the role of cellular mechanisms of transporters and metabolic enzymes is important, but the basics must not be forgotten. This discussion on intestinal physiology is utilised to address those areas which require further research and understanding, and new technologies are highlighted. Better understanding of the fundamental information available can open new avenues for research and pave the way for the future of gastrointestinal drug delivery.

Mucoadhesion and the gastrointestinal tract.

The concept of mucoadhesion is one that has the potential to improve the highly variable residence times experienced by drugs and dosage forms at various sites in the gastrointestinal tract, and consequently, to reduce variability and improve efficacy. Intimate contact with the mucosa should enhance absorption or improve topical therapy. A variety of approaches have been investigated for mucoadhesion in the gastrointestinal tract, particularly for the stomach and small intestine. Despite interesting results in these sites, mucoadhesive approaches have not yet shown success in humans. The potential of the lower gut for these applications has been largely neglected, although the large intestine in particular may benefit, and the colon has several factors that suggest mucoadhesion could be successful there, including lower motility and the possibility of a lower mucus turnover and thicker mucus layer. In vitro studies on colonic mucoadhesion show promise, and rectal administration has shown some positive results in vivo. This review considers the background to mucoadhesion with respect to the physiological conditions of the gastrointestinal tract as well as the principles that underlie this concept. Mucoadhesive approaches to gastrointestinal drug delivery will be examined, with particular attention given to the lower gut.

Interplay between intestinal pH, transit time and feed status on the in vivo performance of pH responsive ileo-colonic release systems.

PURPOSE: Oral pH triggered drug delivery systems, for targeting to the lower gastrointestinal tract, show erratic behaviour in vivo. This study aimed to establish correlations between in situ gastrointestinal pH, transit time or feed status and the disintegration of pH-responsive dosage forms designed to dissolve above pH 7. METHODS: Tablets (radiolabelled with Technetium 99m) coated with Eudragit S were administered to eight healthy subjects in a three-way crossover study after an overnight fast. Food was administered either 30 min after (pre-feed) or 4 h after (fasted) tablet ingestion. Concurrently, a Bravo pH monitoring capsule (radiolabelled with Indium 111) was administered in a "freefall manner". In a third arm of the study tablets were given immediately after breakfast (fed). Transit was followed by gamma scintigraphy. RESULTS: Gastrointestinal pH showed variability between and within individuals but no differences were seen between pre-feed and fasted states. Three tablets failed to disintegrate in pre-feed and fed regimens and one in the fasted state; this has been tentatively linked to ileocaecal pH and ileoceacal junction residence time. CONCLUSIONS: In vivo performance of "pH-responsive" dosage forms is complex and influenced by a multitude of factors other than just in situ pH.

An investigation into the digestion of chitosan (noncrosslinked and crosslinked) by human colonic bacteria.

Chitosan salts are being investigated as materials for bacterially triggered colonic drug delivery, via the oral route, based on the assumption that they will be degraded by the enzymes produced by the human colonic bacteria. The actual susceptibility of chitosan to these enzymes is, however, unclear. The digestion of chitosan films (noncrosslinked, and crosslinked with glutaraldehyde or tripolyphosphate) by human colonic bacteria (using human faecal material) was therefore investigated, and in addition, their digestion by pancreatic enzymes (of porcine origin) was assessed. Noncrosslinked chitosan films were digested by both pancreatic and colonic enzymes within 4 h, while glutaraldehyde crosslinked chitosan films were resistant to both enzyme systems. In contrast, tripolyphosphate crosslinked chitosan films resisted pancreatic digestion, but were susceptible to faecal digestion over the same 4 h time period. As expected, lowering crosslinker concentration and increasing incubation time (to 18 h) allowed greater digestion. The difference between the crosslinkers is attributed to the mechanism of crosslinking, and the associated degree of film swelling in an aqueous environment. Swelling studies in acidic conditions suggest that only glutaraldehyde or higher concentrations of tripolyphosphate would be able to prevent film dissolution in gastric conditions.

Colonic antigen administration induces significantly higher humoral levels of colonic and vaginal IgA, and serum IgG compared to oral administration.

It was hypothesised that different immune responses would be obtained following oral and colonic antigen administration, due to the significant differences in the immune environments of the colon and that of the small intestine. Antigen administration to the mouse colon (via the rectum) was found to generate different profiles of immune responses compared to oral administration (by gavage). Serum IgG and IgA levels in faecal and colonic extracts and in the vaginal wash were significantly higher following colonic administration of soluble (plus cholera toxin B subunit adjuvant) or encapsulated (in microspheres) antigen while smaller differences were seen in the small intestinal IgA levels. This reflects the compartmentalisation within the common mucosal immune system and suggests that the colon may be an appropriate vaccination target for diseases of the colon, and for sexually and vertically transmitted diseases. Antigen was also administered rectally and intramuscularly as controls. Colonic administration was superior to rectal administration, possibly due to the greater amounts of lymphoid tissue in the colon, although the immune response profiles were similar.

Measurements of rat and mouse gastrointestinal pH, fluid and lymphoid tissue, and implications for in-vivo experiments.

To use rodent models effectively in in-vivo investigations on oral drug and vaccine delivery, the conditions in the gastrointestinal tract must be understood. Some fundamental information is currently unavailable or incomplete. We have investigated the pH, water content and lymphoid tissue distribution along the gastrointestinal tract, as well as the stomach volume, as these were critical to our investigations on pH-responsive drug delivery and colonic vaccination. The observed values were compared with those in man as an indication of the validity of the rodent model. The mouse stomach pH was 3.0 (fed) and 4.0 (fasted), and the corresponding values in the rat were 3.2 (fed) and 3.9 (fasted). The mean intestinal pH was lower than that in man (