Pharmacokinetics and pharmacodynamics of 3,3′-diindolylmethane (DIM) in regulating gene expression of phase II drug metabolizing enzymes

3,3′-Diindolylmethane (DIM) has been investigated as a potential anti-cancer chemopreventive agent in many preclinical and clinical studies. In this study, we sought to characterize the pharmacokinetics of DIM and to build a pharmacokinetic (PK) and pharmacodynamic (PD) model of the DIM-induced gene expression of phase II drug metabolizing enzymes (DME), which potentially links DIM’s molecular effects to its in vivo chemopreventive efficacy. DIM (10 mg/kg) was administered intravenously (i.v.) to male Sprague–Dawley rats and blood samples were collected at selected time points for 48 h. The plasma concentration of DIM was determined using a validated HPLC method. The mRNA expression of NQO1, GSTP1 and UGT1A1 in blood lymphocytes was measured using quantitative PCR. An indirect response model was employed to relate the concentration of DIM to the expression of the genes NQO1, GSTP1 and UGT1A1, which were chosen as PD markers for DIM. After i.v. administration, the plasma concentration of DIM declined quickly, and the expression of target genes increased significantly, peaking at 1–2 h and then returning to basal levels after 24 h. The parameters in the PK–PD model were estimated. The PK–PD model aptly described the time delay and magnitude of gene expression induced by DIM. Our results indicate that DIM is effective at inducing various phase II DME, which are capable of detoxify carcinogens. This PK–PD modeling approach provides a framework for evaluating the acute effects of DIM or other similar drugs in clinical trials.     

Population pharmacokinetic analysis of oseltamivir and oseltamivir carboxylate following intravenous and oral administration to patients with and without renal impairment

This work characterizes the pharmacokinetics (PK) of oseltamivir phosphate (OP) and its active metabolite, oseltamivir carboxylate (OC), and investigates oseltamivir i.v. dosing regimens for treatment of influenza in patients with normal renal function and with various degrees of renal impairment. Initially, data collected from 149 subjects with normal renal function and mild to severe renal impairment who were administered 40–200 mg oseltamivir i.v. were described by a four-compartment model. Two compartments described OP, one compartment described OC and one compartment described OP to OC metabolism. Then, data of 128 subjects administered 20–1,000 mg oseltamivir orally were added. The absorption model included three first-order processes with direct (via first-pass) input in the OC compartment and two (direct and delayed) inputs in the OP compartment. Simulations and PK bridging were used to recommend i.v. dosing regimens. The analysis demonstrated that renal function had a major effect on OC clearance (CL _M ) and exposure. CL _M for subjects with mild, moderate and severe renal impairment was 18, 50, and 84 % lower than for subjects with normal renal function. Simulations were used to select i.v. dosing regimens that provide OC C_min coverage and exposures comparable to those achieved in subjects with normal renal function administered 75 mg b.i.d. orally. The oseltamivir dose depended on the degree of renal impairment and was independent of route of administration. Specifically, 75 mg b.i.d. is recommended for subjects with normal renal function or mild renal impairment, 30 mg b.i.d. for subjects with moderate renal impairment, and 30 mg q.d. for subjects with severe renal impairment. Recommended i.v. doses were the same as those recommended for oral administration in corresponding renal impairment groups.     

Deep tissue massage: What are we talking about?

Background

Massage is a common treatment in complementary and integrative medicine. Deep tissue massage, a form of therapeutic massage, has become more and more popular in recent years. Hence, the use of massage generally and deep tissue massage specifically, should be evaluated as any other modality of therapy to establish its efficacy and safety.

Enhanced vasorelaxation effect of endogenous anandamide on thoracic aorta in renal vascular hypertension rats

Emerging evidence has indicated that anandamide (AEA) is able to stimulate vasorelaxation in both spontaneously hypertensive rats (SHRs) and L‐NAME‐induced hypertensive rats. Yet it remains unknown whether AEA modulates vasomotion of the aorta in renovascular hypertensive (RVH) rats. The aim of present study is to explore the effect of AEA on the relaxation of thoracic aortas in two‐kidney one‐clip (2K1C)‐induced RVH rats. It is demonstrated that AEA stimulates a pronounced relaxation in the aortas of 2K1C rats compared with sham rats. The enhanced relaxation caused by AEA in aortas from 2K1C rats was diminished in the presence of the cannabinoid receptor‐1 (CB₁) antagonist AM251 and the CB₂ receptor antagonist AM630. Likewise, the vasodilation action of AEA was blocked in L‐NAME‐treated or endothelium‐denuded aortas. The Western blot results revealed that the expression of CB₁ and CB₂ receptors was increased in the 2K1C rat aortas compared with sham rats. The phosphorylation of endothelial nitric oxide synthase (p‐eNOS) at the activation site Ser1177 was enhanced in AEA‐treated rings from 2K1C rats in both time‐dependent and dose‐dependent manners. The augmented p‐eNOS expression was inhibited by the co‐treatment with AM251 or AM630. Taken together, the present study demonstrated that AEA enhanced endothelium‐dependent aortic relaxation through activation of both CB₁ and CB₂ receptors and P‐eNOS/NO pathway in 2K1C rats.     

Kir6.2 is required for adaptation to stress

Reaction to stress requires feedback adaptation of cellular functions to secure a response without distress, but the molecular order of this process is only partially understood. Here, we report a previously unrecognized regulatory element in the general adaptation syndrome. Kir6.2, the ion-conducting subunit of the metabolically responsive ATP-sensitive potassium (K(ATP)) channel, was mandatory for optimal adaptation capacity under stress. Genetic deletion of Kir6.2 disrupted K(ATP) channel-dependent adjustment of membrane excitability and calcium handling, compromising the enhancement of cardiac performance driven by sympathetic stimulation, a key mediator of the adaptation response. In the absence of Kir6.2, vigorous sympathetic challenge caused arrhythmia and sudden death, preventable by calcium-channel blockade. Thus, this vital function identifies a physiological role for K(ATP) channels in the heart.