Structure‒tissue exposure/selectivity relationship (STR) correlates with clinical efficacy/safety

Drug optimization, which improves drug potency/specificity by structure‒activity relationship (SAR) and drug-like properties, is rigorously performed to select drug candidates for clinical trials. However, the current drug optimization may overlook the structure‒tissue exposure/selectivity-relationship (STR) in disease-targeted tissues vs. normal tissues, which may mislead the drug candidate selection and impact the balance of clinical efficacy/toxicity. In this study, we investigated the STR in correlation with observed clinical efficacy/toxicity using seven selective estrogen receptor modulators (SERMs) that have similar structures, same molecular target, and similar/different pharmacokinetics. The results showed that drug's plasma exposure was not correlated with drug's exposures in the target tissues (tumor, fat pad, bone, uterus), while tissue exposure/selectivity of SERMs was correlated with clinical efficacy/safety. Slight structure modifications of four SERMs did not change drug's plasma exposure but altered drug's tissue exposure/selectivity. Seven SERMs with high protein binding showed higher accumulation in tumors compared to surrounding normal tissues, which is likely due to tumor EPR effect of protein-bound drugs. These suggest that STR alters drug's tissue exposure/selectivity in disease-targeted tissues vs. normal tissues impacting clinical efficacy/toxicity. Drug optimization needs to balance the SAR and STR in selecting drug candidate for clinical trial to improve success of clinical drug development.

Why 90% of clinical drug development fails and how to improve it?

Ninety percent of clinical drug development fails despite implementation of many successful strategies, which raised the question whether certain aspects in target validation and drug optimization are overlooked? Current drug optimization overly emphasizes potency/specificity using structure‒activity-relationship (SAR) but overlooks tissue exposure/selectivity in disease/normal tissues using structure‒tissue exposure/selectivity-relationship (STR), which may mislead the drug candidate selection and impact the balance of clinical dose/efficacy/toxicity. We propose structure‒tissue exposure/selectivity-activity relationship (STAR) to improve drug optimization, which classifies drug candidates based on drug's potency/selectivity, tissue exposure/selectivity, and required dose for balancing clinical efficacy/toxicity. Class I drugs have high specificity/potency and high tissue exposure/selectivity, which needs low dose to achieve superior clinical efficacy/safety with high success rate. Class II drugs have high specificity/potency and low tissue exposure/selectivity, which requires high dose to achieve clinical efficacy with high toxicity and needs to be cautiously evaluated. Class III drugs have relatively low (adequate) specificity/potency but high tissue exposure/selectivity, which requires low dose to achieve clinical efficacy with manageable toxicity but are often overlooked. Class IV drugs have low specificity/potency and low tissue exposure/selectivity, which achieves inadequate efficacy/safety, and should be terminated early. STAR may improve drug optimization and clinical studies for the success of clinical drug development.

Tumor-derived exosomes: Nanovesicles made by cancer cells to promote cancer metastasis

Nanomedicine usually refers to nanoparticles that deliver the functional drugs and siRNAs to treat cancer. Recent research has suggested that cancer cells can also make nanoparticles that also deliver functional molecules in promoting cancer metastasis, which is the leading cause of various cancer mortalities. This nanoparticle is called tumor-derived vesicles, or better-known as tumor-derived exosomes (TEXs). TEXs are nanoscale membrane vesicles (30-140 nm) that are released continuously by various types of cancer cells and contain tumor-derived functional biomolecules, including lipids, proteins, and genetic molecules. These endogenous TEXs can interact with host immune cells and epithelial cells locally and systemically. More importantly, they can reprogram the recipient cells in favor of promoting metastasis through facilitating tumor cell local invasion, intravasation, immune evasion, extravasation, and survival and growth in distant organs. Growing evidence suggests that TEXs play a key role in cancer metastasis. Here, we will review the most recent findings of how cancer cells harness TEXs to promote cancer metastasis through modulating vascular permeability, suppressing systemic immune surveillance, and creating metastatic niches. We will also summarize recent research in targeting TEXs to treat cancer metastasis.

Propagation Characteristics of Fasting Duodeno-Jejunal Contractions in Healthy Controls Measured by Clustered Closely-spaced Manometric Sensors

BACKGROUND/AIMS: High-resolution methods have advanced esophageal and anorectal manometry interpretation but are incompletely established for intestinal manometry. We characterized normal fasting duodeno-jejunal manometry parameters not measurable by standard techniques using clustered closely-spaced recordings. METHODS: Ten fasting recordings were performed in 8 healthy controls using catheters with 3–4 gastrointestinal manometry clusters with 1–2 cm channel spacing. Migrating motor complex phase III characteristics were quantified. Spatial-temporal contour plots measured propagation direction and velocity of individual contractions. Coupling was defined by pressure peak continuity within clusters. RESULTS: Twenty-three phase III complexes (11 antral, 12 intestinal origin) with 157 (95% CI, 104–211) minute periodicities, 6.99 (6.25–7.74) minute durations, 10.92 (10.68–11.16) cycle/minute frequencies, 73.6 (67.7–79.5) mmHg maximal amplitudes, and 4.20 (3.18–5.22) cm/minute propagation velocities were recorded. Coupling of individual contractions was 39.1% (32.1–46.1); 63.0% (54.4–71.6) of contractions were antegrade and 32.8% (24.1–41.5) were retrograde. Individual phase III contractions propagated > 35 fold faster (2.48 cm/sec; 95% CI, 2.25–2.71) than complexes themselves. Phase III complexes beyond the proximal jejunum were longer in duration (P = 0.025) and had poorer contractile coupling (P = 0.025) than proximal complexes. Coupling was greater with 1 cm channel spacing vs 2 cm (P < 0.001). CONCLUSIONS: Intestinal manometry using clustered closely-spaced pressure ports characterizes novel antegrade and retrograde propagation and coupling properties which degrade in more distal jejunal segments. Coupling is greater with more closely-spaced recordings. Applying similar methods to dysmotility syndromes will define the relevance of these methods.

Experimental Study of Effectiveness of Hyperbaric Oxygen Combined with Silybin on Lschemic-reperfused Injured Limbs / 第二军医大学学报

27 rabbits were divided into normal group(n = 4),control group (n = 5), silybin group (n = 6), hyperbaric oxygen (HBO) group (n = 6), and HBO combined with silybin group (n = 6). Circulation of hindlimb was interrupted completely for 6 h and reperfused for 1 h. Malondialdehyde (MDA) and superoxide dismutase(SOD) in plasma from ischemic-reperfused injured limb were measured. Adenosine triphosphate (ATP) and creatine phosphate (CP) in samples taken from anterior tibial muscle were determined. Ultrastructural changes of injured muscle were observed. The results showed that HBO combined with silybin treatment had a favourable effect on ischemic and reperfused injured limb muscle with reduction of the lipid peroxidated injury, increase of the SOD activity and the high energy phosphate compounds (ATP and CP), and a promoting recovery of injured muscle cells. HBO and silybin had a synergistic action. It suggests that HBO combined with silybin is an effective method for treatment of ischemic and reperfused injured limb.

Inhibitory Effect of SZ-1 on the Arachidonic Acid Releases in the Cerebrovascular Endothelial and Smooth Muscle Cells / 第二军医大学学报

The release of platelet activating factor (PAF) induced 14C-arachidonic acid (14C-AA) in the bovine cerebral microvascular endothdial cells (CMEC) and arterior cerebral artery smooth muscle cells (ACASMC) and the antagonism of SZ-1 are described. The results showed that 14C-AA incorporated into the cells rapidly and PAF 0.1-20?mol/L dose-dependently stimulated the AA release significantly. It indicated that the action of PAF on the cerebrovascular system was associated with the stimulation of AA release. SZ-1 0.2-20?nol/L dose-dependently inhibited the PAF induced AA release in CMBC and ACASMC, and PAF induced aggregation of washed rabbit platelets, but did not inhibited ADP or AA induced aggregation of platelet-rich plasma(PRP), and PAF production in CMEC, indicating the specific antagonism of SZ-1 on PAF receptor.

Specific |3H|LTC4 Receptors on Intact Smooth Muscle Gells Derived from Bovine Cerebral Microvasculatures / 第二军医大学学报

Specific receptors for leukotriene C4 LTC4 have been identified on intact smooth muscle cells derived from bovine cerebral microvasculatures. Specific pHJLTC4, binding at a fixed input at 25 ℃ was rapid , reaching the maximum at 20min With incremental inputs of radioligand and a constant cell number, specific [3H]LTC4 binding reached a plateau indicative of a saturable binding site. Analysis of Scatchard plots demonstrated a single high affinity binding site with a dissociation constant (Kd) of 2.01?0.4 nmol/L and Bmax = 156.6?13.1 fmol/106 cells. The specific [3H]LTC4 binding could be inhibited by unlabted LTC4, LTD4 and FPL-55712 with an inhibitory rate of 96.9%, 73.9% and 44.9% at 10-5 mol/L, respectively.