Middle East respiratory syndrome coronavirus (MERS-CoV) is the causative agent of a severe respiratory disease associated with more than 2468 human infections and over 851 deaths in 27 countries since 2012. There are no approved treatments for MERS-CoV infection although a combination of lopinavir, ritonavir and interferon beta (LPV/RTV-IFNb) is currently being evaluated in humans in the Kingdom of Saudi Arabia. Here, we show that remdesivir (RDV) and IFNb have superior antiviral activity to LPV and RTV in vitro. In mice, both prophylactic and therapeutic RDV improve pulmonary function and reduce lung viral loads and severe lung pathology. In contrast, prophylactic LPV/RTV-IFNb slightly reduces viral loads without impacting other disease parameters. Therapeutic LPV/RTV-IFNb improves pulmonary function but does not reduce virus replication or severe lung pathology. Thus, we provide in vivo evidence of the potential for RDV to treat MERS-CoV infections.

/pdf/comparative-therapeutic-efficacy-of-remdesivir-and-21uo6ry619.pdf

Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

/pdf/consensus-guidelines-for-therapeutic-drug-monitoring-in-18b8y5mu39.pdf

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.

Cytosolic sensing of pathogens and damage by myeloid and barrier epithelial cells assembles large complexes called inflammasomes, which activate inflammatory caspases to process cytokines (IL-1β) and gasdermin D (GSDMD). Cleaved GSDMD forms membrane pores, leading to cytokine release and inflammatory cell death (pyroptosis). Inhibiting GSDMD is an attractive strategy to curb inflammation. Here we identify disulfiram, a drug for treating alcohol addiction, as an inhibitor of pore formation by GSDMD but not other members of the GSDM family. Disulfiram blocks pyroptosis and cytokine release in cells and lipopolysaccharide-induced septic death in mice. At nanomolar concentration, disulfiram covalently modifies human/mouse Cys191/Cys192 in GSDMD to block pore formation. Disulfiram still allows IL-1β and GSDMD processing, but abrogates pore formation, thereby preventing IL-1β release and pyroptosis. The role of disulfiram in inhibiting GSDMD provides new therapeutic indications for repurposing this safe drug to counteract inflammation, which contributes to many human diseases.

FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation

https://escholarship.org/content/qt9xb8q5z6/qt9xb8q5z6.pdf?t=q7c1km

Psychedelics Promote Structural and Functional Neural Plasticity

A significant fraction of patients with advanced prostate cancer treated with androgen deprivation therapy experience relapse with relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC). Immune checkpoint blockade using antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PD-L1) generates durable therapeutic responses in a significant subset of patients across a variety of cancer types. However, mCRPC showed overwhelming de novo resistance to immune checkpoint blockade, motivating a search for targeted therapies that overcome this resistance. Myeloid-derived suppressor cells (MDSCs) are known to play important roles in tumour immune evasion. The abundance of circulating MDSCs correlates with prostate-specific antigen levels and metastasis in patients with prostate cancer. Mouse models of prostate cancer show that MDSCs (CD11b+Gr1+) promote tumour initiation and progression. These observations prompted us to hypothesize that robust immunotherapy responses in mCRPC may be elicited by the combined actions of immune checkpoint blockade agents together with targeted agents that neutralize MDSCs yet preserve T-cell function. Here we develop a novel chimaeric mouse model of mCRPC to efficiently test combination therapies in an autochthonous setting. Combination of anti-CTLA4 and anti-PD1 engendered only modest efficacy. Targeted therapy against mCRPC-infiltrating MDSCs, using multikinase inhibitors such as cabozantinib and BEZ235, also showed minimal anti-tumour activities. Strikingly, primary and metastatic CRPC showed robust synergistic responses when immune checkpoint blockade was combined with MDSC-targeted therapy. Mechanistically, combination therapy efficacy stemmed from the upregulation of interleukin-1 receptor antagonist and suppression of MDSC-promoting cytokines secreted by prostate cancer cells. These observations illuminate a clinical path hypothesis for combining immune checkpoint blockade with MDSC-targeted therapies in the treatment of mCRPC.

/pdf/effective-combinatorial-immunotherapy-for-castration-41mvag1pns.pdf

Effective combinatorial immunotherapy for castration-resistant prostate cancer.

Understanding the concept of extrapolation of dose between species is important for pharmaceutical researchers when initiating new animal or human experiments. Interspecies allometric scaling for dose conversion from animal to human studies is one of the most controversial areas in clinical pharmacology. Allometric approach considers the differences in body surface area, which is associated with animal weight while extrapolating the doses of therapeutic agents among the species. This review provides basic information about translation of doses between species and estimation of starting dose for clinical trials using allometric scaling. The method of calculation of injection volume for parenteral formulation based on human equivalent dose is also briefed.

/pdf/a-simple-practice-guide-for-dose-conversion-between-animals-30qgwlcg8u.pdf

A simple practice guide for dose conversion between animals and human.

Preclinical Research & Development Appropriate translation and determination of the maximum recommended starting dose in human is a vital task in new drug development and research. Allometric scaling is the most frequently used approach for dose extrapolation based on normalization of dose-to-body surface area. Misinterpretation of allometric dose conversion and safety factor application can lead to major problems in calculating maximum recommended safe starting dose in first-in-human clinical trials. Therefore, dose translation always necessitates careful consideration of body surface area, pharmacological, physiological and anatomical factors, pharmacokinetic parameters, metabolic function, receptor, and life span. The concept of estimating the first-in-human dose, interspecies scaling between species and the factors influencing the dose escalation were reviewed. The pros and cons of various approaches to determine first-in-human dose including allometric scaling, pharmacokinetically guided approach, minimal anticipated biological effect level, pharmacokinetic-pharmacodynamic modeling, similar drug approach, and microdosing were explained. The five steps to estimate maximum recommended starting dose for human studies by scaling factor were elaborated. Few examples, illustrating the application of different approaches were also demonstrated along with concerns that may be considered while applying such methods. Furthermore, typical considerations in dose administration, dosing through diet, maximum absorbable dose, blood sampling, and anesthesia in animal species were discussed. In summary, this review may serve as a concise guide for predicting human equivalent dose from animal species for researchers involved in various phases of preclinical and early clinical drug development.

Dose translation between laboratory animals and human in preclinical and clinical phases of drug development.

Rapid advancement in drug discovery process is leading to a number of potential new drug candidates having excellent drug efficacy but limited aqueous solubility. By virtue of the submicron particle size and distinct physicochemical properties, nanosuspension has the potential ability to tackle many formulation and drug delivery issues typically associated with poorly water and lipid soluble drugs. Conventional size reduction equipment such as media mill and high-pressure homogenizers and formulation approaches such as precipitation, emulsion-solvent evaporation, solvent diffusion and microemulsion techniques can be successfully implemented to prepare and scale-up nanosuspensions. Maintaining the stability in solution as well as in solid state, resuspendability without aggregation are the key factors to be considered for the successful production and scale-up of nanosuspensions. Due to the considerable enhancement of bioavailability, adaptability for surface modification and mucoadhesion for drug targeting have significantly expanded the scope of this novel formulation strategy. The application of nanosuspensions in different drug delivery systems such as oral, ocular, brain, topical, buccal, nasal and transdermal routes are currently undergoing extensive research. Oral drug delivery of nanosuspension with receptor mediated endocytosis has the promising ability to resolve most permeability limited absorption and hepatic first-pass metabolism related issues adversely affecting bioavailability. Advancement of enabling technologies such as nanosuspension can solve many formulation challenges currently faced among protein and peptide-based pharmaceuticals.

/pdf/emerging-role-of-nanosuspensions-in-drug-delivery-systems-4mgplri7zl.pdf

Emerging role of nanosuspensions in drug delivery systems.

Given the distinctive characteristics of both epilepsy and antiepileptic drugs (AEDs), therapeutic drug monitoring (TDM) can make a significant contribution to the field of epilepsy. The measurement and interpretation of serum drug concentrations can be of benefit in the treatment of uncontrollable seizures and in cases of clinical toxicity; it can aid in the individualization of therapy and in adjusting for variable or nonlinear pharmacokinetics; and can be useful in special populations such as pregnancy. This review examines the potential for TDM of newer AEDs such as eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, perampanel, pregabalin, rufinamide, retigabine, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide. We describe the relationships between serum drug concentration, clinical effect, and adverse drug reactions for each AED as well as the different analytical methods used for serum drug quantification. We discuss retrospective studies and prospective data on the serum drug concentration–efficacy of these drugs and present the pharmacokinetic parameters, oral bioavailability, reference concentration range, and active metabolites of newer AEDs. Limited data are available for recent AEDs, and we discuss the connection between drug concentrations in terms of clinical efficacy and nonresponse. Although we do not propose routine TDM, serum drug measurement can play a beneficial role in patient management and treatment individualization. Standardized studies designed to assess, in particular, concentration–efficacy–toxicity relationships for recent AEDs are urgently required.

/pdf/an-updated-overview-on-therapeutic-drug-monitoring-of-recent-4qunlcn7up.pdf

An Updated Overview on Therapeutic Drug Monitoring of Recent Antiepileptic Drugs.

Co-processed particles of microcrystalline cellulose and mannitol were fabricated by spray drying technique to be used as a direct compression excipient in fast dissolving tablet formulation. Microcrystalline cellulose passed through sieve no.80, having a volumetric mean diameter (d 50 ) of 28.35 µm, was used to form composite particles with powdered mannitol which was previously passed through sieve no. 80, in various mixing ratios. The composite particles were evaluated for their powder and compression properties. An increase in the microcrystalline cellulose proportion imparted greater compressibility to the composite particles, but the flowability of these mixtures was decreased. Although microcrystalline cellulose and mannitol have been extensively used in the formulation of fast dissolving tablets, the non-wetting property of the hard compact central core may delay the disintegration time. Optimized co-processed formulation containing mannitol and microcrystalline cellulose in the ratio of 1.25:1 was found to have optimized powder and compressibility characteristics with fast disintegrating property (<15 s). Photomicrographs have shown that the mannitol crystals are fine and uniformly distributed in the microcrystalline matrix in spray dried form compared to physical mixture of the same combination. The fast disintegration may be due to the partial amorphization and formation of submicron particles of mannitol. These results indicated that improved fast dissolving tablets could be prepared by the co-processed mixture of microcrystalline cellulose and mannitol. Finally fast dissolving tablets of glipizide were prepared by blending with other excipients and compressed into tablets. Sensory study on disintegration time and mouth feel attributes ranked the present formulation based on grittiness, chalkiness and overall preference as the best.

https://www.ijpsonline.com/articles/novel-coprocessed-excipients-of-mannitol-and-microcrystalline-cellulose-for-preparing-fast-dissolving-tablets-of-glipizi.pdf

Shery Jacob

Papers

A simple practice guide for dose conversion between animals and human.

Dose translation between laboratory animals and human in preclinical and clinical phases of drug development.

Emerging role of nanosuspensions in drug delivery systems.

An Updated Overview on Therapeutic Drug Monitoring of Recent Antiepileptic Drugs.

Novel co-processed excipients of mannitol and microcrystalline cellulose for preparing fast dissolving tablets of glipizide