Eudragit®: a technology evaluation

Introduction: Eudragit is the brand name for a diverse range of polymethacrylate-based copolymers. It includes anionic, cationic, and neutral copolymers based on methacrylic acid and methacrylic/acrylic esters or their derivatives.

Areas covered: In this review, the physicochemical characteristics and applications of different grades of Eudragit in colon-specific/enteric-coated/sustained release drug delivery and taste masking have been addressed.

Expert opinion: Eudragits are amorphous polymers having glass transition temperatures between 9 to > 150^oC. Eudragits are non-biodegradable, nonabsorbable, and nontoxic. Anionic Eudragit L dissolves at pH > 6 and is used for enteric coating, while Eudragit S, soluble at pH > 7 is used for colon targeting. Studies in human volunteers have confirmed that pH drops from 7.0 at terminal ileum to 6.0 at ascending colon, and Eudragit S based systems sometimes fail to release the drug. To overcome the shortcoming, combination of Eudragit S and Eudragit L which ensures drug release at pH < 7 has been advocated. Eudragit RL and RS, having quaternary ammonium groups, are water insoluble, but swellable/permeable polymers which are suitable for the sustained release film coating applications. Cationic Eudragit E, insoluble at pH ≥ 5, can prevent drug release in saliva and finds application in taste masking.     

Information and communication technology in chronic diseases: a patient’s opportunity

The increasing aging population, the prevalence of chronic diseases and rising costs have brought about some unique health care challenge to our global society. In response to the unmet health care needs, researchers are actively seeking for innovative solutions that target for (1) prevention of diseases and (2) personalized diagnosis and treatment. It is envisaged that by taking preventive measures for health monitoring, diagnosing and treating patients with a personalized approach at an early stage of disease development, health care will be more cost effective and sustainable. The authors provide an overview of the advancements in Information and Communication Technology (ICT), and explain how some innovative health solutions, through the use of Telemedicine, can now be an opportunity for patients and their family.     

Cypher® versus Taxus®: the stent war

Cypher^® (sirolimus-eluting stent) and Taxus^® (paclitaxel-eluting stent) have been approved for use in percutaneous coronary intervention. Both of the stents have shown superiority over bare metal stents in reducing major adverse cardiac events, restenosis rates and target vessel revascularisation. Results of clinical trials with head-to-head comparison of Taxus and Cypher stents in patients with obstructive coronary artery diseases have recently been reported. This review compares the performance of Cypher and Taxus stents as noted in observational studies and clinical trials in various types of coronary artery lesions.     

Colostrinin™: a naturally occurring compound derived from mammalian colostrum with efficacy in treatment of neurodegenerative diseases,including Alzheimer's

Neurodegenerative illnesses such as Alzheimer's disease and their debilitating effects pose a major problem as their incidence increases. Although clinical management of neurodegenerative diseases usually involves symptomatic treatment, Colostrinin^? (CLN), which has efficacy in counteracting neural degradation and in stimulating neural growth, might prove to be a more effective means to deal with the causes of Alzheimer's and other neurodegenerative diseases. Evidence for the clinical efficacy of CLN is discussed and recent data examined showing the remarkable ability of CLN to reduce oxidative stress, prevent β-amyloid aggregation and prolong the lifespan in a laboratory model of premature ageing. An increasingly important application for CLN has been as a nutraceutical product for use in the early stages of cognitive decline in humans, with licensed use in North America and Australia, and now in Europe. It might also be of considerable utility as a veterinary nutraceutical for companion animals.     

Generation of proliferating human hepatocytes using upcyte® technology: characterisation and applications in induction and cytotoxicity assays

1. We have developed a novel technique which causes primary human hepatocytes to proliferate by transducing them with genes that upregulate their proliferation.

2. Upcyte^® hepatocytes did not form colonies in soft agar and are not immortalised anchorage-independent cells. Confluent cultures expressed liver-specific proteins, produced urea and stored glycogen.

3. CYP activities were low but similar to that in 5-day cultures of primary human hepatocytes. CYP1A2 and CYP3A4 were inducible; moreover, upcyte^® hepatocytes predicted the in vivo induction potencies of known CYP3A4 inducers using the “relative induction score” prediction model. Placing cells into 3D culture increased their basal CYP2B6 and CYP3A4 basal activities and induction responses.

4. Phase 2 activities (UGTs, SULTs and GSTs) were comparable to activities in freshly isolated hepatocytes.

5. Upcyte^® hepatocytes were markedly more sensitive to the hepatotoxin, α-amanitin, than HepG2 cells, indicating functional OATP1B3 uptake. The cytotoxicity of aflatoxin B₁, was decreased in upcyte^® hepatocytes by co-incubation with the CYP3A4 inhibitor, ketoconazole. Upcyte^® hepatocytes also differentiated between ten hepatotoxic and eight non-hepatotoxic compounds.

6. In conclusion, upcyte^® hepatocyte cultures have a differentiated phenotype and exhibit functional phase 1 and 2 activities. These data support the use of upcyte^® hepatocytes for CYP induction and cytotoxicity screening.

     

Selective targeting of synthetic antioxidants to mitochondria: towards a mitochondrial medicine for neurodegenerative diseases?

Mitochondria are the major source of superoxide, and are responsible for activating apoptosis and oxidative damage during acute neuronal cell death and neurodegenerative disorders like Alzheimer and Parkinson diseases. While the molecular mechanisms by which mitochondrial oxidative stress triggers apoptosis are still investigated, attempts to achieve neuroprotection using antioxidant molecules have already been successful in several models of neuronal cell death. To increase the availability of antioxidant drugs at the mitochondrial level within cells, Michael P. Murphy recently proposed to covalently couple antioxidant molecules to a membrane-permeable lipophilic cation serving as carrier. Since mitochondria maintain at rest a potential of -180 mV, the diffusible cationic moiety drives the accumulation of the complex inside the matrix towards a diffusion equilibrium: for a monovalent cationic carrier, a thousand-fold accumulation of the complex is theoretically achievable; for a divalent cation, a million-fold accumulation is expected. Such mitochondria-targeted versions of natural antioxidants have successfully been synthesized and were found to counteract the pro-apoptotic effects of exogenous oxidative insults, while having no effects in models mimicking physiological apoptosis. Based on these observations, we carried out the synthesis of targeted variants of the artificial free radical scavengers 4-hydroxy-2,2,6,6-tetramethylpiperidin-N-oxide (TEMPOL) and Salen-Mn(III) complex of o-vanillin (EUK-134). Our preliminary results indicate that these targeted compounds, while delaying apoptosis after an exogenous oxidative insult, are not more active than their untargeted variants. This questions the general efficiency of the targeting procedure used and/or suggests that the main pro-apoptotic effector targets of exogenous oxidative insults are not located within mitochondria.     

Metabolism of the thiocarbamate herbicide SUTAN® in rats

1. The metabolism of the thiocarbamate herbicide SUTAN° (butylate) was studied after administration of single oral doses of [isobutyl-1-¹⁴C]SUTAN to male and female rats.

2. The radiolabelled dose was rapidly absorbed and excreted, with 79% of the dose excreted in the urine in 72?h. The small percentages of radioactivity excreted in the faeces and as ¹⁴CO₂ were significantly higher (P≤0.05) in males than in females.

3. SUTAN was extensively metabolized, and no unmetabolized SUTAN was found in the urine. A total of 18 of the 29 urinary metabolites were identified, and identified metabolites represented 83–88% of the urinary radioactivity.

4. Diisobutylamine was the major urinary metabolite in both males and females, averaging 51% of the urinary radioactivity.

5. Other significant urinary metabolites included primary hydroxylated and tertiary hydroxylated diisobutylamines and a series of mercapturic acid pathway metabolites, including an S-glucuronide and several hydroxylated and unhydroxylated mercapturates.

6. Oxidations at the three alkyl groups produced a variety of minor urinary metabolites, and hydroxylation of the primary or tertiary carbon on the isobutyl groups, followed by an intramolecular reaction, generated a series of minor cyclized metabolites.     

Mitochondria targeting drugs for neurodegenerative diseases—Design,mechanism and application

Neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) are a heterogeneous group of disorders characterized by progressive degeneration of neurons. NDDs threaten the lives of millions of people worldwide and regretfully remain incurable. It is well accepted that dysfunction of mitochondria underlies the pathogenesis of NDDs. Dysfunction of mitochondria results in energy depletion, oxidative stress, calcium overloading, caspases activation, which dominates the neuronal death of NDDs. Therefore, mitochondria are the preferred target for intervention of NDDs. So far various mitochondria-targeting drugs have been developed and delightfully some of them demonstrate promising outcome, though there are still some obstacles such as targeting specificity, delivery capacity hindering the drugs development. In present review, we will elaborately address 1) the strategy to design mitochondria targeting drugs, 2) the rescue mechanism of respective mitochondria targeting drugs, 3) how to evaluate the therapeutic effect. Hopefully this review will provide comprehensive knowledge for understanding how to develop more effective drugs for the treatment of NDDs.     

Salmon calcitonin-loaded Eudragit® and Eudragit®-PLGA nanoparticles: in vitro and in vivo evaluation

The main objective of this study was to prepare salmon calcitonin (sCT)-loaded Eudragit®RSPO, Eudragit®L100 and Eudragit®-poly(lactic-co-glycolic acid) blend nanoparticles for in vitro and in vivo evaluation as an oral drug delivery system. The prepared nanoparticles ranged in size from 179.7 to 308.9?nm with a polydispersity index between 0.051 and 2.75, and had surface charges ? ?11 to +6?mV. Efficient sCT encapsulation and release was observed with all the nanoparticle formulations. The polymer type was an important factor that influenced the release characteristics and the in vivo hypocalcemic effect. Nanoparticle formulations were also prepared with sodium taurodeoxycholate (NaTDC) and characterized. No statistically significant difference was noted between the hypocalcemic effect of any of the nanoparticle formulations with and without NaTDC (p?>?0.05). The use of Eudragit®RSPO nanoparticles appears to be a potential approach for the oral delivery of sCT.     

Interrupting apoptosis in neurodegenerative disease: potential for effective therapy?

Current treatment options for neurodegenerative diseases are limited and mainly affect only the symptoms of disease. Because of the unknown and probably multiple causes of these diseases, they cannot be readily targeted. However, it has been established that apoptosis contributes to neuronal loss in most neurodegenerative diseases. A possible treatment option is to interrupt the signaling networks that link neuronal damage to apoptotic degradation in neurodegeneration. The viability of this option depends upon the extent to which apoptosis accounts for neuron loss, whether or not interruption of apoptosis signaling results in recovery of neurological function and whether or not there are significant downsides to targeting apoptosis. Several compounds acting at different sites in known apoptotic signaling networks are currently in development and a few are in clinical trial. If an apoptosis-targeted compound succeeds in slowing or halting neurological dysfunction in one or more neurodegenerative diseases, a new era in the treatment of neurodegenerative diseases will begin.     

Pediatric gastrointestinal diseases: are drugs the answer?

Owing to the lack of large randomized controlled studies, which would produce level 1 evidence, to guide management of gastrointestinal disorders in children, data are often extrapolated from adult studies to aid in treatment strategies. However, there are unique aspects to the management of children and adolescents with these chronic diseases, including issues of growth, side effects, long-term outcomes and psychosocial factors that might not be considered in adult trials. There is a major need for increased research in this population. In the future, a better understanding of the pathophysiologic mechanisms of these diseases should guide the development of rational novel therapies with better safety profiles for children with gastrointestinal disorders.     

Adverse drug reactions in patients with gastroenterological diseases: does age increase the risk?

BACKGROUND: It has been claimed that the risk of adverse drug reactions increases with age. However, only limited data exist for disease-group specific risks and none for patients with liver and gastrointestinal diseases. AIMS: To determine the incidence and characteristics of adverse drug reactions and the physicians' awareness of adverse drug reactions. METHODS: During a 7-month period, a prospective survey of 532 male patients (158 aged 65 years or older; 30%) was conducted on a hepatogastroenterological ward of a tertiary-care university hospital, using intensive bedside and computer-assisted drug surveillance methods. RESULTS: No difference was found in the overall rate of adverse drug reactions between older and younger patients (25.9% vs. 24.2%) during 6213 treatment days. However, a significantly higher risk for developing adverse drug reactions could be shown for the elderly with biliary tract diseases (P < 0.01). Independently of age, patients suffering from gastric ulcers, acute episodes of pancreatitis, cholangitis or inflammatory bowel diseases were at high risk of adverse drug reactions. Adverse drug reaction-associated mortality was encountered in four elderly and none of the younger patients. Secondary pharmacological effects and drug toxicity were the main types of adverse drug reactions for both age groups. Although 75.3% of the adverse drug reactions were predictable, only 37.5% of all adverse drug reactions were recognized by the staff physicians. CONCLUSION: In hepatogastroenterological patients, advancing age was not associated with an overall increased risk of adverse drug reactions except for patients with biliary tract diseases. In the elderly, adverse drug reactions were more severe and carried higher mortality. Guidelines and educational programs should be developed to increase the awareness of adverse drug reactions and their prevention, especially in high risk patients and, thus, to improve patient outcomes.     

Salmon calcitonin-loaded Eudragit® and Eudragit®-PLGA nanoparticles: in vitro and in vivo evaluation

The main objective of this study was to prepare salmon calcitonin (sCT)-loaded Eudragit?RSPO, Eudragit?L100 and Eudragit?-poly(lactic-co-glycolic acid) blend nanoparticles for in vitro and in vivo evaluation as an oral drug delivery system. The prepared nanoparticles ranged in size from 179.7 to 308.9?nm with a polydispersity index between 0.051 and 2.75, and had surface charges ~ -11 to +6?mV. Efficient sCT encapsulation and release was observed with all the nanoparticle formulations. The polymer type was an important factor that influenced the release characteristics and the in vivo hypocalcemic effect. Nanoparticle formulations were also prepared with sodium taurodeoxycholate (NaTDC) and characterized. No statistically significant difference was noted between the hypocalcemic effect of any of the nanoparticle formulations with and without NaTDC (p?>?0.05). The use of Eudragit?RSPO nanoparticles appears to be a potential approach for the oral delivery of sCT.     

Genetic testing of children for adult-onset diseases: is testing in the child's best interests?

Questions related to testing children for adult-onset genetic diseases include many variables that generate different answers among different families. These issues include the biological nature of specific genes, concern about what benefits or harms may accrue from testing children, possible psychosocial sequelae, and ethical and legal concerns about personal autonomy. The shift in the physician-patient relationship from professional beneficence to patient autonomy has established the patient, or parents, as the primary decision-makers in questions about treatment or testing options. The role of parents as decision-makers for their own minor children has been reinforced by four seminal holdings of the United States Supreme Court. Assertions about protecting the future autonomy of children are invalid because minor children are not autonomous. Their parents, on the other hand, have a right--and perhaps even a duty--to exercise their own vested autonomy in making decisions that they believe are in the best interests of their own families. Geneticists are urged to provide clear and complete counseling to parents who seek testing for their children, and then defer to the parents as the primary decision-makers for their own minor children.