A semi-mechanistic dose-finding design in oncology using pharmacokinetic/pharmacodynamic modeling.

While a number of phase I dose-finding designs in oncology exist, the commonly used ones are either algorithmic or empirical model-based. We propose a new framework for modeling the dose-response relationship, by systematically incorporating the pharmacokinetic (PK) data collected in the trial and the hypothesized mechanisms of the drug effects, via dynamic PK/PD modeling, as well as modeling of the relationship between a latent cumulative pharmacologic effect and a binary toxicity outcome. This modeling framework naturally incorporates the information on the impact of dose, schedule and method of administration (e.g., drug formulation and route of administration) on toxicity. The resulting design is an extension of existing designs that make use of pre-specified summary PK information (such as the area under the concentration-time curve [AUC] or maximum serum concentration [Cmax ]). Our simulation studies show, with moderate departure from the hypothesized mechanisms of the drug action, that the performance of the proposed design on average improves upon those of the common designs, including the continual reassessment method (CRM), Bayesian optimal interval (BOIN) design, modified toxicity probability interval (mTPI) method, and a design called PKLOGIT that models the effect of the AUC on toxicity. In case of considerable departure from the underlying drug effect mechanism, the performance of the design is shown to be comparable with that of the other designs. We illustrate the proposed design by applying it to the setting of a phase I trial of a γ-secretase inhibitor in metastatic or locally advanced solid tumors. We also provide R code to implement the proposed design.

Treatment of tibial dyschondroplasia with traditional Chinese medicines: "Lesson and future directions".

Tibial dyschondroplasia (TD) is a metabolic tibiotarsal bone disease in rapidly growing birds throughout the world, which is characterized by gait disorders, reduced growth, and in an unrecoverable lameness in many cases. The short production cycle in chickens, long metabolism cycle in most of the drugs with the severe drug residue, and high treatment cost severely restrict the enthusiasm for the treatment of TD. Traditional Chinese medicine (TCM) has been used for the prevention, treatment, and cure of avian bone diseases. Previously, a couple of traditional Chinese medicines has been reported being useful in treating TD. This review will discuss the TCM used in TD and the alternative TCM to treat TD. Selecting a TCM approach and its pharmacologic effects on TD chickens mainly focused on the differentiation, proliferation, and apoptosis of chondrocytes, angiogenesis, matrix metabolism, oxidative damage, cytokines, and calcification of cartilage in tibia.

Safety, Pharmacokinetics, and Pharmacodynamics of ME-401, an Oral, Potent, and Selective Inhibitor of Phosphatidylinositol 3-Kinase P110δ, Following Single Ascending Dose Administration to Healthy Volunteers.

PURPOSE: ME-401 is a novel selective inhibitor of phosphatidylinositol 3 kinase p110δ, an enzyme often found overexpressed and overactive in B-cell malignancies. The current study was performed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending oral doses of ME-401 in healthy volunteers. METHODS: This analysis was an open-label, nonrandomized study in healthy male volunteers. Three sequential groups were dosed. Each group received single doses of ME-401 on two occasions; the doses tested ranged from 10 to 150 mg. Blood was drawn at various time points to analyze plasma concentrations of ME-401 and inhibition of basophil activation, a marker of phosphatidylinositol 3 kinase p110δ inhibition. FINDINGS: Fifteen subjects received a single dose of ME-401 on two occasions. Three adverse events that were considered possibly related to the study drug were reported: one event of pain, one event of headache, and one event of upper abdominal pain. ME-401 exhibited dose proportionality up to 60 mg, and supra-proportional increases in exposure were observed above doses of 60 mg. In addition, there was a dose-proportional increase in the inhibition of basophil activation up to 60 mg. Mean t1/2 ranged from 9.36 to 29.23 hours across the dose range. A 60 mg dose of ME-401 approached 90% inhibition of basophil activation, and thereafter no further increase to the percent inhibition of basophil activation was observed for higher doses. Once-daily dosing of 60 mg ME-401 was forecasted to result in trough plasma levels exceeding the concentration needed for 90% inhibition of basophil activation. IMPLICATIONS: This first-in-human study showed that ME-401 was well tolerated after single doses up to 150 mg. Pharmacologic activity was confirmed after administration of single ascending oral doses of 10 to 150 mg. ME-401 60 mg, administered once daily, was selected as the starting dose for patient studies. ClinicalTrials.gov identifier: NCT02521389.

Research progress on vascular pharmacologic effect of salidroside / 药物评价研究

Salidroside antagonizes hypoxia,H2O2,hyper-glucose,homocysteine,smoking,orweightlessness-induced endothelial cell injury,and antagonizes the proliferation of vascular smooth muscle cells and vascular adventitial fibroblasts induced by hypoxia,hyper-glucose,noradrenaline,platelet-derived growth factor,or angiotensin Ⅱ,thus produces vascular protection and improves vascular function.Salidroside plays a dual role of vasoconstriction and vasodilation in regulating resistant blood vessel.The vasodilatory effect of salidroside is endothelium-dependent and endothelium-independent.Salidroside antagonizes vascular contraction and injury induced by KC1,CaC12,noradrenaline,phenylephrine,homocysteine,hyper-glucose,plateau hypoxia,H2O2,and chlorine.Salidroside relieves cerebral vasospasm induced by subarachnoid hemorrhage,and pulmonary hypertension and pulmonary arterial remodeling induced by hypoxia or monocrotaline in rat,attenuates several experimental atherosclerosis,and enhances plaque stability.

Research progress on vascular pharmacologic effect of salidroside / 药物评价研究

Salidroside antagonizes hypoxia,H2O2,hyper-glucose,homocysteine,smoking,orweightlessness-induced endothelial cell injury,and antagonizes the proliferation of vascular smooth muscle cells and vascular adventitial fibroblasts induced by hypoxia,hyper-glucose,noradrenaline,platelet-derived growth factor,or angiotensin Ⅱ,thus produces vascular protection and improves vascular function.Salidroside plays a dual role of vasoconstriction and vasodilation in regulating resistant blood vessel.The vasodilatory effect of salidroside is endothelium-dependent and endothelium-independent.Salidroside antagonizes vascular contraction and injury induced by KCl,CaCl2,noradrenaline,phenylephrine,homocysteine,hyper-glucose,plateau hypoxia,H2O2,and chlorine.Salidroside relieves cerebral vasospasm induced by subarachnoid hemorrhage,and pulmonary hypertension and pulmonary arterial remodeling induced by hypoxia or monocrotaline in rat,attenuates several experimental atherosclerosis,and enhances plaque stability.

Research advance on pharmacokinetics of oleanolic acid / 药物评价研究

Oleanolic acid has a widespread pharmacologic effect,including anti-inflammation,antitumor,anfidiabetes,anti-atherosclerosis,hepatoprotection,anti-osteoporosis,etc.Bioavailability of oleanolic acid by oral administration is low,and is absorbed by intestine through passive transport.Oleanolic acid dispersion preparation can increase its solubility and bioavailability,and concentrate on liver to help treat for hepatic disease.The pharmacokinetic parameters,process in body of oleanolic acid,and the pharmacokinetic feature of oleanolic acid dispersion and its prodrug are reviewed,and its research advance on pharmacokinetics is summarized,which provides a reference for rational utilization of oleanolic acid.

Vitamins and Minerals in Alternative Medicine / 日本補完代替医療学会誌

This review deals with the role of micronutrients, i.e. vitamins and minerals, in alternative medicine. The following two conditions are important when considering vitamins and minerals as tools for alternative medicine: (1) The majority of Japanese consume less than the dietary requirement of vitamins and essential minerals. A national nutrition survey in 2001 showed that vitamins B ₁, B₆, C, and E, calcium, magnesium, iron, zinc and copper could be included in this category. (2) Micronutrients have a specific pharmacological effect that is independent of their nutritional function. Vitamins A, D, E, K, B₁, B₁₂, and C, magnesium, iron, zinc, copper, lithium and vanadium are included in this category. In addition, vitamin-like active substances may be used as an alternative medicine for their pharmacologic actions. The function and role of each micronutrient in alternative medicine is discussed.<br>