Purpose.

The aim of this study was to correlate the relationship between the pharmacokinetic behaviors and the toxicity of a new investigational anticancer agent CZ48, a C20-propionate ester of camptothecin (CPT) in mice. Methods. In this study, the safety and pharmacokinetics of oral doses of CZ48 were compared with the oral doses of CPT. Mice were administered orally one of three single doses of CZ48 (50, 200 and 1000 mg/kg) and two single doses of CPT (1.5 mg/kg and 6.0 mg/kg). Blood samples were collected from all mice at the defined time points after drug administration for assessment of plasma CZ48 and CPT concentrations.

Results.

The study showed that CZ48 was very stable in mouse blood and the majority of this agent stayed intact as the lactone form when in circulation, with only a small fraction of the CZ48 molecules metabolized into CPT. The concentration of the metabolite CPT measured in the mouse blood was only 3% of the concentration found for the maximum tolerated dose (6.0 mg/kg) of plain CPT. The stability difference between CZ48 and CPT in blood was structurally explained by the geometry of these two molecules.

Conclusion.

The lack of toxicity of CZ48 at effective doses in mice is attributed to its enhanced stability in their blood. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on

ABSTRACT

on the issue's contents page.

Purpose.

Chromium (Cr) as an essential trace element in metabolism of carbohydrate, lipid and protein is currently prescribed to control diabetes mellitus (DM). The objective of this meta-analysis was to compare the effect of Cr versus placebo (Pl) on glucose and lipid profiles in patients with type 2 DM. Methods. Literature searches in PubMed, Scopus, Scirus, Google Scholar and IranMedex was made by use of related terms during the period of 2000-2012. Eligible studies were randomized clinical trials (RCTs) with intake of Cr higher than 250 µg at least for three months in type 2 DM. Glycated hemoglobin (HbA1c), fasting blood sugar (FBS), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), triglyceride (TG), and body mass index (BMI) were the main outcomes.

Results.

Seven out of 13 relevant studies met the criteria and were included in the meta-analysis. HbA1c change in diabetic patients in Cr supplement therapy comparing to Pl was -0.33 with 95%CI= -0.72 to 0.06 (P= 0.1). Change of FBG in Cr therapy vs. Pl was -0.95 with 95%CI= -1.42 to -0.49 (P< 0.0001). TC change in Cr therapy vs. Pl was 0.07 with 95%CI= -0.16 to 0.31 (P= 0.54). TG change in diabetic patients in Cr supplement therapy comparing to Pl was -0.15 with 95%CI= -0.36 to 0.07 (P= 0.18).

Conclusions.

Cr lowers FBS but does not affect HbA1c, lipids and BMI. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on

ABSTRACT

on the issue's contents page.

Purpose.

To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of acetazolamide (ACTZ) in peritoneal dialysis patients, ACTZ 500 mg was administered intravenously to 7 healthy subjects (HV) and 8 peritoneal dialysis patients (CAPD). Methods. Population PK/PD modeling was performed with ACTZ serum (total and unbound), urine and dialysate concentrations, intra-ocular pressure (IOP) and covariates. A multi-compartment PK model (accounting for non-linear protein binding) and an inhibitory Emax (maximal change in IOP) PD model were selected.

Results.

As expected, renal clearance (which almost equals total body clearance) was severely decreased in CAPD (1.2 vs 80.3 L/h) and the elimination half-life of total ACTZ was prolonged (20.6 vs 3.4 hours). The protein binding was significantly altered with a mean free fraction 4.2% in HV and 8.6% in CAPD. Moreover protein binding of ACTZ was concentration dependent in both HV and CAPD. Despite a higher free fraction of ACTZ, the Emax was lower in CAPD: 4.4±1.4 vs 7.4±2.8 mmHg.

Conclusion.

Both PK and PD are significantly altered in dialysis patients. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on

ABSTRACT

on the issue's contents page.

Venous thromboembolism (VTE) is a serious disease that is often neglected, and effective and safe antithrombotic treatments are a public health priority. New antithrombotics such as rivaroxaban, apixaban, betrixaban, edoxaban, darexaban, TAK-442, LY517717, eribaxaban, otamixaban are being developed to overcome current therapeutic limitations. The new oral anticoagulants and parenteral otamixaban are under evaluation in clinical trials for VTE treatment, for VTE prevention in orthopedic surgery, for stroke prevention in patients with atrial fibrillation and for cardiovascular event prevention in patients with acute coronary syndrome. These antithrombotic agents directly and selectively inhibit factor Xa, and do not require coagulation monitoring and dose adjustment. Several of these drugs have shown promising results and have the potential to either replace or act as alternatives to traditional anticoagulants (heparins, vitamin K antagonists). This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on

ABSTRACT

on the issue's contents page.

Purpose:

The induction of hyperlipidemia using poloxamer 407 (P407) is gaining use for studying the effect of the condition on drug pharmacokinetics. Although a single intraperitoneal dose of P407 causes a rapid onset of hyperlipidemia, the initial lipid concentrations are much higher than seen in humans. The hyperlipidemia is also reversible in nature. Here, pharmacokinetic methods were used to assess the P407 dose response on serum lipids, adipokines and cytokines.

Methods:

Single 0.5 and 1 g/kg doses of P407 were injected into rats followed by blood collection at various times for up to 12 d. Serum was assayed for lipids, selected adipokines and cytokines.

Results:

As expected, large increases in lipid levels were seen by 36 h after dosing. Using area under the concentration vs. time curve as a measure of systemic lipid exposure, P407 increased serum baseline corrected serum lipids in a nearly dose proportional fashion. The maximum increase in lipids was observed at ~36 h, with most lipids remaining elevated for up to ~180 h, although for the 1 g/kg dose triglyceride concentrations had still not quite returned to baseline by 12 days postdose. In addition to changes in lipids, P407 significantly increased serum leptin and decreased the serum adiponectin concentrations but did not affect cytokine levels.

Conclusion:

Depending on study aims, for the use of the model it may be beneficial to perform single-dose assessments at time points later than 36 h when the lipoprotein concentrations will be more similar to those seen in patient with hyperlipidemia. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on

ABSTRACT

on the issue's contents page.

Purpose.

We investigated elemental strontium and/or bisphosphonate drug incorporation upon the compositional and biomechanical properties of vertebral bone, in a rat model of Osteoporosis secondary to ovariectomy. Methods. Six month old female rats were ovariectomized (OVX) and divided into untreated OVX-Vehicle, OVX-RIS (Risedronate bisphosphonate [BP] treated), OVX-SrR (Strontium Ranelate [Protos®] treated), combination OVX-RIS+SrR, and sham-operated controls. After 16 weeks of treatment, rats were euthanized and lumbar vertebra were dissected. Micro-Computed Tomography (micro-CT), Electron Probe Micro-Analysis (EPMA), mechanical testing in compression and nano-indentation testing were then undertaken to evaluate bone morphometry, elemental composition, material properties and strength.

Results.

Bone Volume was significantly reduced in the OVX-Vehicle (133±10mm3) compared with OVX-RIS (169±22mm3), OVX-SrR (145±2mm3), and OVX-RIS+SrR (172±8mm3). EPMA mapped elemental Sr deposition to the periosteal surface of cortical bone (50-100 µm thick), endosteal trabecular surfaces (20 µm thick), as well as to both vertebral growth plates. The atomic ratios of (Ca+Sr)/P were significantly reduced with SrR treatment (2.4%-6.6%), indicating Sr incorporation into bone mineral. No significant differences were measured in vertebral bone reduced modulus by nano-indentation. Conversely, all BP-dosed groups had significantly increased structural bone strength.

Conclusions.

Thus, we conclude that BP drugs dominate the conservation of trabecular geometry and structural strength in OP rats, whereas Sr drugs likely influence bone volume and material composition locally. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on

ABSTRACT

on the issue's contents page.

Purpose.

The aim of this study was to prepare a new neovascularity targeting antitumor drug delivery system mediated by single-walled carbon nanotubes (SWNTs). Methods. In this study, antiangiogenesis agent 2-methoxyestradiol was loaded by SWNTs via π~π accumulation. The SWNTs were then linked with NGR (Asn-Gly-Arg) peptide, which could target tumor angiogenesis. This drug delivery system was characterized by transmission electron microscope, scanning electron microscopy, and atomic force microscope analysis. The suppression efficacy of tumor growth in cultured breast cancer cell line was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The in vivo antitumor activity was evaluated on the Sarcoma (S180) tumor-bearing mice model.

Results.

The characteristics of this drug delivery system showed that the particle of complex was 190 ± 4.3 nm in size distribution and 23.56 ± 2.03 mV in zeta potential. The inhibition ratio of this SWNTs drug delivery system at 24, 48, and 72 h was about 57.7%, 83.6%, and 88.2%. Compared with normal saline group, the relative tumor volumes in the 2ME, SWNTs-2ME, and NGR-SWNTs-2ME groups were decreased 1 week after administration.

Conclusion.

This novel neovascularity targeting drug delivery system containing NGR-SWNTs-2ME may be beneficial to improve treatment efficacy and minimize side effects in future cancer therapy. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on

ABSTRACT

on the issue's contents page.

Ischemic heart disease is the second leading cause of death in the world. The proportion of deaths resulting from this condition has decreased in the last two decades, mainly as a result of improved primary and secondary prevention of cardiovascular events, as well as the development of patient awareness and medical and pharmacological management. The purpose of the present review is to analyze pathophysiological events leading to platelet involvement in cardiovascular thrombosis, as well as the role of pharmacogenetics in modulating the risk of cardiovascular disorders. The present work was performed using a PubMed search with combinations of key words relevant to the subject in both English and French. In addition to the pharmacokinetic and pharmacodynamic characteristics of platelet inhibitors, this work reviews the efficacy and adverse events observed during the clinical trials with these drugs. This review further summarizes possible therapeutic drug monitoring strategies for antiplatelet drugs. The novelty of this work is the description of the lymphocyte toxicity assay as a specific method of diagnosing and predicting possible idiosyncratic adverse events attributable to antiplatelet medication. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on

ABSTRACT

on the issue's contents page.

To compare the properties of buccal delivery matrices (wafers) made with dextrin, β-limit dextrin and pre-gelatinised starch.The constituent α-glucans were tested for their mucoadhesive properties in solution plus their content of crystalline material (differential scanning calorimetry, DSC). Wafers were made by lyophilisation of aqueous solutions/dispersions of the α-glucans. Physical properties of the wafers were evaluated using texture analysis, dissolution coupled to photography and scanning electron microscopy (SEM).The results highlighted how the β-limit dextrins chemical and physical properties were ideally suited for the production of buccal delivery wafers. Dissolution testing confirmed the excellent hydration profile of the β-limit dextrin (within wafers) with time. Using SEM it was evident that the homogeneous "bee-hive" like structure of the β-limit dextrin wafers, unlike the other α-glucans, provided a rapidly hydratable strong porous matrix.The β-limit dextrin α-glucan makes a superb (lyophilised) mucoadhesive delivery structure for the delivery of active agents to the buccal mucosa.

Harmaline is one member of a class of tremorgenic harmala alkaloids that have been implicated in neuroprotective effects and neurodegenerative disorders. It has been reported to interact with several neurotransmitter receptors as well as ion exchangers and voltage-sensitive channels. One site of harmaline action in the brain is the inferior olive (IO). Either local or systemic harmaline injection has been reported to increase spiking rate and coherence in the inferior olive and this activation is thought to produce tremor and ataxia through inferior olivary neuron activation of target neurons in the cerebellum, but the cellular mechanism is not yet known.Here, we have performed whole cell voltage-clamp and current clamp recordings from olivary neurons in brain slices derived from newborn rats.We found that both transient low-voltage activated (LVA) and sustained high voltage-activated (HVA) Ca(2+) currents are significantly attenuated by 0.125 - 0.25 mM harmaline applied to the bath and that this attenuation is partially reversible. In current clamp recordings, spike-afterhyperpolarization complexes were evoked by brief positive current injections. Harmaline produced a small attenuation of spike amplitude, but large spike broadening associated with attenuation of the fast and medium afterhyperpolarization.Our data suggest that one mode of olivary neuron activation by harmaline involves attenuation of both HVA and LVA Ca(2+) conductances and consequent attenuation of Ca(2+)-sensitive K(+) conductances resulting in spike broadening and attenuation of the afterhyperpolarization. Both of HVA and LVA attenuation also suggests a role to regulate intracelluar Ca(2+), thereby to protect neurons from apoptosis.