Recent advances and clinical pharmacology aspects of Chimeric Antigen Receptor (CAR) T‐cellular therapy development

Advances in immuno‐oncology have provided a variety of novel therapeutics that harness the innate immune system to identify and destroy neoplastic cells. It is noteworthy that acceptable safety profiles accompany the development of these targeted therapies, which result in efficacious cancer treatment with higher survival rates and lower toxicities. Adoptive cellular therapy (ACT) has shown promising results in inducing sustainable remissions in patients suffering from refractory diseases. Two main types of ACT include engineered Chimeric Antigen Receptor (CAR) T cells and T cell receptor (TCR) T cells. The application of these immuno‐therapies in the last few years has been successful and has demonstrated a safe and rapid treatment regimen for solid and non‐solid tumors. The current review presents an insight into the clinical pharmacology aspects of immuno‐therapies, especially CAR‐T cells. Here, we summarize the current knowledge of TCR and CAR‐T cell immunotherapy with particular focus on the structure of CAR‐T cells, the effects and toxicities associated with these therapies in clinical trials, risk mitigation strategies, dose selection approaches, and cellular kinetics. Finally, the quantitative approaches and modeling techniques used in the development of CAR‐T cell therapies are described.     

Accumulation of Cadmium in Transplanted Lichen Pyxine cocoes (Sw.) Nyl., with Reference to Physiochemical Variation and Kinetics of Cadmium Biosorption

Bulletin of Environmental Contamination and Toxicology - The safe utilization and risk assessment of produced water (PW) from oil and gas fields for desert irrigation have received increasing...     

Mammillary body atrophy in acute liver failure and acute-on-chronic liver failure of nonalcoholic etiology

The most common cause of atrophy of mammillary bodies (MBs) is thiamine deficiency, which is very common in patients with alcoholic liver disease. The purpose of this study was to look for changes in MBs using brain magnetic resonance imaging (MRI) in patients with acute liver failure (ALF), acute-on-chronic liver failure (ACLF) and chronic liver failure (CLF) of non-alcoholic etiology. Volumes of MBs and caudate nuclei (CNs) were quantified in nine patients with ALF, 17 with ACLF, 18 with CLF and in 24 healthy controls. Volume of these structures was quantified again three weeks after clinical recovery in five patients with ALF who had survived their illness. Volume of left, right and both MBs was significantly decreased (p < 0.05) in patients with ALF and ACLF whereas there was no change in patients with CLF, when compared with healthy controls. However CN volumes did not change significantly compared to controls in any of the three patient groups. In the follow-up study significant recovery in volume of MBs was noted compared to baseline values in the ALF patients. We conclude that significant volume loss occurs in MBs in patients with ALF and ACLF of non-alcoholic etiology but not in CLF. This loss of MBs volume recovers substantially in patients with ALF who survive their illness.     

Characterization of total plasma glycosaminoglycan levels in healthy volunteers following oral administration of a novel antithrombotic odiparcil with aspirin or enoxaparin

Odiparcil is a novel, orally active beta-d-thioxyloside analog with antithrombotic activity associated with a reduced risk of adverse bleeding events. Its unique mechanism of action is postulated by means of an elevation in circulating endogenous chondroitin sulfate-related glycosaminoglycans (GAGs) levels. The purpose of these 2 separate clinical studies was to evaluate plasma GAG levels in healthy subjects administered odiparcil with either aspirin (ASA) or enoxaparin. Clinical plasma samples were processed and analyzed using validated HPLC bioassays that indirectly estimate GAG levels based on the simultaneous detection of the chondroitin disaccharide derivatives. The concomitant administration of odiparcil with or without ASA resulted in a significant elevation in GAG levels over baseline for both treatment groups. In the other clinical study, the concomitant administration of odiparcil with or without enoxaparin displayed significant increases in plasma DeltaDi-OS, DeltaDi-4S, and total disaccharide levels versus control group. Neither plasma GAG levels nor odiparcil plasma levels were correlated with a rise in hepatic transaminases, an adverse drug event observed in several subjects; and plasma odiparcil levels were indirectly correlated with plasma GAG levels. These clinical studies were proof of concept of preclinical rat studies indicating that chronic odiparcil treatment elevates endogenous GAG levels in human subjects.     

Biowaiver approach for biopharmaceutics classification system class 3 compound metformin hydrochloride using in silico modeling

The dependency of metformin in vivo disposition on the rate and extent of dissolution was studied. The analysis includes the use of fundamental principles of drug input, permeability, and intestinal transit time within the framework of a compartmental absorption transit model to predict key pharmacokinetic (PK) parameters and then compare the results to clinical data. The simulations show that the maximum plasma concentration (C_max) and area under the curve (AUC) are not significantly affected when 100% of drug is released within 2 h of oral dosing, which was confirmed with corresponding human PK data. Furthermore, in vitro dissolution profiles measured in aqueous buffers at pH values of 1.2, 4.5, and 6.8 were slower than in vivo release profiles generated by deconvolution of metformin products that were bioequivalent. On the basis of this work, formulations of metformin that release 100% in vitro in a   time period equal to or less than two hours are indicated to be bioequivalent. The use of modeling offers a mechanistic-based approach for demonstrating acceptable bioperformance for metformin formulations without having to resort to in vivo bioequivalence studies and may be more robust than statistical comparison of in vitro release profiles. This work further provides a strategy for considering Biopharmaceutics Classification System (BCS) Class 3 compounds to be included under biowaiver guidelines as for BCS Class 1 compounds. © 2012Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:1773–1782, 2012     

Abortion law reform in Nepal

Across four decades of political and social action, Nepal changed from a country strongly enforcing oppressive abortion restrictions, causing many poor women’s long imprisonment and high rates of abortion-related maternal mortality, into a modern democracy with a liberal abortion law. The medical and public health communities supported women’s rights activists in invoking legal principles of equality and non-discrimination as a basis for change. Legislative reform of the criminal ban in 2002 and the adoption of an Interim Constitution recognizing women’s reproductive rights as fundamental rights in 2007 inspired the Supreme Court in 2009 to rule that denial of women’s access to abortion services because of poverty violated their constitutional rights. The government must now provide services under criteria for access without charge, and services must be decentralized to promote equitable access. A strong legal foundation now exists for progress in social justice to broaden abortion access and reduce abortion stigma.     

Optimal utilization of pediatric computed tomography to minimize radiation exposure: What the clinician must know

The number of computed tomography (CT) scans being done for children all over the world is on the rise ever since the advent of Multi-Detector CT (MDCT). However, CT is a potential source of harmful ionizing radiation, and children are more susceptible to its adverse effects. It is essential for the pediatrician as well as the radiologist to be aware of some important principles and guidelines, by following which, radiation exposure to the child can be minimized to the bare essential. It is important to have knowledge of the valid and justifiable indications of CT for the child, the correct technique of performing the scan, and the new technological innovations now available on modern scanners that help to minimize radiation dose.     

A Water Extract from Chlorella sorokiniana Cell Walls Stimulates Growth of Bone Marrow Cells and Splenocytes

A water extract derived from the isolated cell walls of Chlorella sorokiniana (C. sorokiniana, Chlorella water extract, CWE) was analyzed for the presence of lipopolysaccharide (LPS)-related material via the Limulus amebocyte lysate (LAL) assay and evaluated for its growth stimulation effect on the bone marrow cells and splenocytes in vitro cell cultures. The extract contained low levels of LPS-related material, and a mass spectrum suggested that the extract contained many components, including a low level of a lipid A precursor, a compound known as lipid X, which is known to elicit a positive response in the LAL assay. Treatment with the CWE dose- and time-dependently stimulated the growth of mouse bone marrow cells (BMCs) and splenocytes (SPLs). Treatment with the CWE also increased specific BMC subpopulations, including antigen-presenting cells (CD19⁺ B cells, 33D1⁺ dendritic cells and CD68⁺ macrophages), and CD4⁺ and CD8⁺ T cells, but decreased the number of LY6G⁺ granulocytes. Treatment with the CWE also increased cytokine mRNA associated with T cell activation, including TNFα, IFNγ, and granzyme B in human lymphoblasts. The present study indicates that the cell wall fraction of C. sorokiniana contains an LPS-like material and suggests a candidate source for the bioactivity that stimulates growth of both innate and adaptive immune cells.