Protein delivery to the back of the eye: barriers, carriers and stability of anti-VEGF proteins.

Utilization of the full clinical potential of many novel therapeutic proteins designed for diseases affecting the posterior segment of the eye has often been limited because of their inherent instability and the difficulty in overcoming various ocular barriers. Intravitreal injection is currently the only approved mode of administration, although it is suboptimal because it is painful and has to be done every 1-2 months as a result of high protein clearance rates from the vitreous humor. In this review, we discuss the status of protein drug delivery to back of the eye in terms of novel protein drugs developed, physiological barriers encountered, strategies for carrier design to overcome these limitations, and protein stability. We focus on the most promising approaches as well as on current shortcomings.

Impact of CYP2D6 and CYP3A4 genetic polymorphism on combined cholinesterase inhibitors and memantine treatment in mild to moderate Alzheimer's disease.

AIM: The impact of CYP2D6 and CYP3A4 polymorphism on the steady-state plasma concentrations and therapeutic outcome of donepezil monotherapy and combination therapy in Alzheimer's disease (AD) patients. METHODS: A total of 38 patients for donepezil and 17 patients for donepezil and memantine therapy, aged ≥ 55 years, were recruited meeting inclusion and exclusion criteria. Polymerase chain reaction-restriction fragment length polymorphism was performed. The liquid chromatography-tandem mass spectrometry method was used for estimation of drug levels of donepezil and memantine. RESULTS: Significant allele frequency was observed for CYP2D6*3 polymorphism in patients on donepezil monotherapy and combination therapy. Significant allele frequency for CYP2D6*4 was observed in the patients on donepezil monotherapy. CONCLUSION: CYP2D6 polymorphism, though not significant, might partially be involved in the plasma concentration of AD drug.

Val66Met polymorphism and BDNF levels in Alzheimer's disease patients in North Indian population.

Analysis of serum brain-derived neurotrophic factor (BDNF) levels in Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI) and controls with BDNF gene polymorphism and cognitive function were investigated. The study recruited 63 AD patients, 15 aMCI and 63 age- and sex-matched healthy controls from All India Institute of Medical Sciences, New Delhi, India. Patients with AD (12268.3 ± 7099.9 pg BDNF/ml) and aMCI (10780 ± 4184.2 pg BDNF/ml) had higher serum levels than had the controls (9362.833 ± 5883.32 pg BDNF/ml). Significant difference in BDNF levels was not found between the three groups. No significant difference was obtained between BDNF genotype and allele distribution between AD patients, aMCI versus controls; genotypic frequency: Chi-square = 3.21; p-value = 0.20 and allelic frequency: Chi-square = 0.412, p-value = 0.521, df = 1 (AD vs controls); Chi-square = 1.63, p-value = 0.201, df = 1 (aMCI vs controls). In conclusion, val66met polymorphism and BDNF serum level between the three groups and genotype did not significantly affect the serum BDNF level or age, Mini-Mental State Examination score in AD and aMCI. Further studies are necessary to elucidate the kinetics and the potential role of serum BDNF as a marker of disease progression in AD patients.

Clinical effectiveness of rivastigmine monotherapy and combination therapy in Alzheimer's patients.

BACKGROUND: Rivastigmine is an acetylcholinesterase inhibitor; the genotype data seen alongside the phenotype data explain the mutation or the molecular genetics involved and also help to relate the phenotype of an individual with their genotype. AIM: To determine the clinical effectiveness of CYP2D6, CYP3A4, CYP2C9/19, and UGT polymorphism on the steady-state plasma concentrations and therapeutic outcome of rivastigmine monotherapy and combination therapy in patients with Alzheimer's disease. RESULT: In this study, a significant allele frequency was observed for CYP2D6*3 polymorphism in patients under rivastigmine combination therapy (A>del = 0.50 [patients] and A>del = 0.20 [controls]), UGT2B7 (T = 0.17 [patients] and 0.33 [Controls], and UGT1A9*5 A = 0.58 [patients] and 0.26 [Controls]). The drug levels and P value of responders/nonresponders were found to be 0.17 ± 0.08/0.22 ± 0.16 and 0.574 for rivastigmine and 0.18 ± 0.11/0.66 ± 0.63 and 0.009 for rivastigmine in combination therapy and 1.40 ± 0.65/0.59 ± 0.84 and 0.05 for memantine in combination therapy. CONCLUSION: Poor metabolizer subjects of UGT2B7 polymorphism in patients under rivastigmine combination therapy have higher drug levels with a poor response to the drug treatments.

Analytical profiling of bioactive constituents from herbal products, using metabolomics--a review.

Natural products have been the source of many active substances in drug discovery. There are several strategies/approaches in the field of biology, drug discovery, molecular and cell biology for identification of bioactive molecules. Metabolomics involves fewer complexities, is more precise and provides more relevant data compared with other techniques. This approach is based on the application of new technologies and provides real-world end points that complement and help in the interpretation of genomic and proteomic data in drug discovery. It has also been proven to be a valuable analytical tool for the identification of secondary metabolites from medicinal plants, particularly for evidence-based development of new phytotherapeutical agents and nutraceuticals. This review outlines the different analytical techniques used to detect and measure the multiplexed metabolites and biomarkers in the herbal field.