Monoclonal antibodies for the management of central nervous system diseases: clinical success and future strategies.

INTRODUCTION: Recombinant monoclonal antibodies (mAbs) are highly selective and effective biologicals with proven utility as therapeutics. mAbs have demonstrated substantial promise in the treatment of several central nervous system diseases. AREAS COVERED: Databases including PubMed and Clinicaltrials.gov were used to identify clinical studies of mAbs involving patients with neurological disorders. This manuscript reviews the current status and recent advances in the development and engineering of therapeutic blood-brain barrier (BBB)-crossing mAbs and their potential in treatment of central nervous system diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), brain tumors, and neuromyelitis optica spectrum disorder (NMSOD). In addition, the clinical implications of recently developed monoclonal antibodies are also discussed, along with the strategies to enhance their BBB permeability. The adverse events associated with the administration of monoclonal antibodies are also presented in the manuscript. EXPERT OPINION: There is growing evidence that supports the therapeutic utility of monoclonal antibodies in central nervous system and neurodegenerative diseases. Several studies have offered evidence of clinical efficacy in AD through use of anti-amyloid beta antibodies and anti-tau passive immunotherapy-based strategies. Additionally, ongoing research trials have produced promising findings for the treatment of brain tumors and NMSOD.

Process development for the total synthesis of the novel drug metabolite Carboxy toremifene as a standard reference material along with characterization and purity assessment for the Antidoping quality Control Purposes.

Tamoxifen and toremifene are two selective estrogen receptor modulators (SERMs) commonly used to treat breast cancer in women. Toremifene is well-known as a triphenylethylene derivative. Carboxy toremifene is a common metabolite of toremifene and tamoxifen. Since 2005, the World Anti-Doping Agency (WADA) has banned the SERMs category during in and out of competition. These substances are in the S4 category in the WADA prohibited list as "agents with anti-oestrogenic activity." However, there is no commercially accessible carboxy toremifene reference material in the market. This research highlights the novel synthetic procedure, the development of a carboxy toremifene HPLC method, and validation, along with detailed characterization using advanced analytical techniques using 1 H NMR, HRMS, FT-IR-ATR and UV-visible spectroscopy. RP-HPLC-DAD method was developed and validated to assess the purity of carboxy toremifene. Developed reference material has shown 100% purity. Therefore, we recommend that this synthesized carboxy toremifene may be used as reference material to strengthen the WADA-accredited lab to maintain a clean sports mission during sports competitions.

Needle-free cutaneous delivery of living human cells by Er:YAG fractional laser ablation.

BACKGROUND: Dermatological diseases, including most skin cancers and rare genetic conditions frequently originate in the epidermis. Targeted, topical cell-based therapy is a promising therapeutic strategy. Here, we present the first report demonstrating that fractional laser ablation enables local 'needle-free' intraepidermal delivery of living human cells. METHODS: The cells penetrated porcine ear skin via microchannels created by Er:YAG fractional laser ablation; cell delivery was quantified using a haemocytometer. Cutaneous distribution was confirmed visually by laser scanning confocal microscopy and histological analysis. RESULTS: Total cell delivery (sum of amounts permeated and deposited) after 24 h increased from 5.7 ± 0.1 x105 to 9.6 ± 1.6 x105 cells/cm2 when increasing pore density from 300 to 600 pores/cm2, - corresponding to 19- and 32-fold increases over the control. At 600 pores/cm2, cell deposition was 136-fold greater than cell permeation - the latter most likely due to transport from micropores into appendageal pathways. Production of GFP post-delivery confirmed cell remained viability. CONCLUSION: The results demonstrate the feasibility of using controlled laser microporation to achieve local 'needle-free' cutaneous delivery of living human cells to the epidermis and dermis. This raises the possibility of using this technique for targeted new approaches for dermatological therapy in these regions.

Response surface methodology of nitrilase production by recombinant Escherichia coli

Growth and nitrilase production by recombinant Escherichia coli cells harbouring pET 21 (b) plasmid, for the expression of Pseudomonas putida nitrilase were improved using response surface methodology. Central composite design was used for obtaining ideal concentration of critical medium components which include fructose, tryptone, yeast extract and lactose. The optimal values for the concentration of fructose, tryptone, yeast extract and lactose were found to be 1.13, 2.26, 3.25 and 0.9 percent (w/v), respectively. Here, fructose served as carbon source for the growth while lactose was preferably used as inducer for the expression of foreign protein. Yeast extract in the medium was used as a growth promoter while tryptone was added as a major nitrogen source. Using this optimized medium, an experimental growth of 6.67 (OD at 600 nm) and nitrilase activity of 27.13 U/ml was achieved. This approach for medium development led to an enhancement of the growth and enzyme activity by 1.4 and 2.2 times, respectively, as compared to the un-optimized medium.