Multivesicular liposome formulations for the sustained delivery of ropivacaine hydrochloride: Preparation,characterization, and pharmacokinetics

The aim of the present study was to design a depot delivery system of ropivacaine hydrochloride using multivesicular liposomes (RP-MVLs) to overcome the limitations of conventional therapies and to investigate it’s in vivo effectiveness for sustained delivery. RP-MVLs were prepared by the multiple emulsion method. Appearance, particle size, encapsulation efficiency, zeta potential, and initial stability of RP-MVL were also studied. The in vitro release of RP-MVLs formulations was found to be in a sustained manner. Three batches of RP-MVLs were prepared and the release profile in vitro fitted to a first-order equation. RP-MVLs releasing mechanism was also studied and it was indicated that the drug released from MVLs by diffusion and erosion. Following subcutaneous administration to rats, the time to reach maximum (T_max) of RP-MVLs formulations was significantly (p?<?0.01) later than that of RH solution. The concentrations of RP-MVLs have steadily changed in the low level, which significantly (p?<?0.01) lower than RH solution. T_1/2 and MRT were significantly prolonged (p?<?0.01). Besides, AUC was also increased significantly (p?<?0.01). The increase in AUC and decrease in C_max reflects that the MVL formulations could reduce the toxic complications and limitations of conventional injected formation therapies.     

Development toxicity of functionalized single-walled carbon nanotubes on rare minnow embryos and larvae

Abstract

Carbon nanotubes (CNTs) are widely used in industrial and commercial applications, but few studies systematically evaluate their developmental toxicity on aquatic organism. Using rare minnow (Gobiocypris rarus) at early life stages as experimental models, developmental toxicity of functionalized single-walled CNTs (SWCNTs) was investigated following exposure to 0–320?mg/L for 144?h. Results revealed that significantly increased in mortality and malformation was only observed after hatching. Decreased body length, heart rate and swimming speed provide a concentration-dependent manner on larvae; values of 144?h LC₅₀ and EC₅₀ were 140.8 and 109.8?mg/L, respectively. Antioxidant enzyme activities (superoxide dismutase, catalase and glutathione S-transferase) and antioxidant enzyme related mRNA expressions were significant changed; cell apoptosis activities (caspase-3, -8, -9) and cell apoptosis related mRNA expressions were significant up-regulated; reactive oxygen species and DNA damage were significantly induced when the concentration of SWCNTs above 100?mg/L. Fluorescence and electron microscopy sliced observation show that SWCNTs were well dispersed in larvae within 0.5?h, eventually cleared from the larvae at 144?h. This is the first study to define uptake kinetics and to focus on behavioral consequences, physiological changes and mRNA expression following SWCNTs exposure in the early life stages of fish. The results obtained in the present study demonstrated that functionalized SWCNTs have the potential to affect aquatic life when released into the aquatic environment and reached high concentration. In the increasing economical context of SWCNTs, complementary studies must be undertaken, especially including mechanistic and environmental investigations.     

Oxybutynin chloride: alterations in drug delivery and improved therapeutic index

A number of diverse antidepressants with different mechanisms of action are available today. However, the mechanisms of action of US FDA-approved antidepressants still mainly rely on targeting monoamine neurotransmitters. The inadequate remission and response rates achieved by antidepressant treatment for depression have been well known through a number of manufacturer-sponsored randomized, placebo-controlled, clinical trials (RCTs), independent RCTs, some large practical clinical trials and many meta-analyses. In the light of the limited efficacy of currently available antidepressants and the need for an antidepressant with a novel mechanism of action, the availability of agomelatine is prudent and timely for clinical practice. Although agomelatine has been approved for the treatment of depression in Europe and some other countries, its clear efficacy has been questionable based on results from individual RCTs and meta-analyses. However, agomelatine may be more beneficial in specific populations such as those who suffer from unwanted adverse events (AEs) (i.e., sexual dysfunction) by current antidepressants or elderly populations who are vulnerable to AEs. Based on currently available findings, agomelatine may not be recommendable as the first-line antidepressant for treating depression; especially, its putative benefits compared with other antidepressants must be thoroughly studied in adequately powered and well-designed future clinical trials.     

Possible Mechanism for the Relaxant Effect of Pimpinella anisum. on Guinea Pig Tracheal Chains

ABSTRACT

Pimpinella anisum. L. is a grassy plant that is believed to have several therapeutic effects including antiasthmatic uses. In a previous study, the relaxant (bronchodilatory) effect of this plant on isolated guinea pig tracheal chains was demonstrated. To study mechanisms responsible for this effect, the inhibitory effect of this plant on contracted tracheal chains of guinea pig was evaluated in the current study. The relaxant effects of aqueous and ethanol extracts and essential oil from P. anisum. compared to negative controls (saline for aqueous extract and essential oil and ethanol for ethanol extract) and positive control (diltiazem) were examined on precontracted isolated tracheal chains of the guinea pig by 10?µM methacholine (group 1) and 60?mM KCl (group 2, n?=?7 for each group). In group 1 experiments, diltiazem, both extracts, and essential oil from P. anisum. showed significant relaxant effect on methacholine-induced contraction of tracheal chains compared to those of negative controls (p?<?0.05 to p?<?0.001). In addition, the effects of extracts were significantly greater than that of diltiazem (for aqueous and ethanol extracts p?<?0.05 and p?<?0.01, respectively). However, in group 2 experiments, only diltiazem and ethanol extract showed significant relaxant effects on KCl-induced contraction of tracheal chains (p?<?0.05 for ethanol extract and p?<?0.001 for diltiazem). Relaxant effects of extracts and essential oil obtained in group 2 experiments were significantly lower than those of group 1 (p?<?0.05 to p?<?0.001). These results confirm the bronchodilatory effects of extracts and essential oil from P. anisum.. However, with regard to the effect of KCl on calcium channels, the results indicated that inhibitory effect of only ethanol extract from P. anisum. on calcium channels may contribute to its relaxant (bronchodilatory) effects on guinea pig tracheal chains. In addition, the results suggest a potassium channel opening effect for this plant, which may contribute on its relaxant effect on tracheal chains of guinea pig.     

Drug Release from Film-Coated Chlorpheniramine Maleate Nonpareil Beads: Water Influx and Development of a New Drug Release Model

The purpose of this work was to investigate drug release from film-coated chlorpheniramine maleate (CPM) nonpareils (sugar spheres) and the effect of water influx on the drug release mechanism. The methods used in the study involved the layering of CPM onto nonpareil cores using a fluid-bed apparatus. These CPM cores were then coated with an aqueous ethylcellulose dispersion, which was blended with a solution of hydroxylpropylmethylcellulose (HPMC) at different concentrations. The net water influx was determined by measuring water uptake during dissolution. The film surface area was calculated from bead diameters measured with an optical microscope. Drug release profiles were measured using USP dissolution method I (basket). The results showed that significant water influx occurred, which produced an internal liquid phase ranging from 0 to 1.8 × 10³ mm³/g of sample. As a result of the water uptake, an increase in bead size was observed. The bead surface area varied over the range of 40–80 × 10³ mm²/g sample because of a combined effect of the water uptake and the release of the bead contents. A bead geometry parameter was proposed as the ratio of the bead surface area to the volume of the internal liquid phase. This bead geometry parameter was measured as a function of time and fit to an equation using a computer curve-fitting technique. This equation was substituted into an existing drug release model to give a more appropriate mathematical model describing drug release from this system. The conclusion drawn from these results is that the influx of water during drug dissolution creates a progressive increase in the liquid phase within the nonpareil bead; this causes a corresponding increase in the bead surface area which influences the drug release rate.     

A Multi‐mechanistic Drug Release Approach in a Bead Dosage Form and In Vivo Predictions

Our previous study has successfully prepared a combination of immediate release, enteric coated, and controlled release (CR) beads and mathematically modeled in vitro drug release characteristics of the combination based on the release profiles of individual beads. The objectives of the present study are to evaluate the combination and individual beads in vivo and to mathematically model in vivo drug input characteristics of the combination based on the in vivo input of individual beads. Beagle dogs were used as an animal model, and theophylline as a model drug. In vivo percent drug absorbed at different times (input function) after administration of a capsule bead dosage form was calculated using the Wagner–Nelson deconvolution method using intravenous injection of theophylline in each dog as a reference. The in vivo input functions of individual beads were each fitted to appropriate mathematical equations. The in vivo input function of the bead combination dosage form was calculated based on the individual mathematical equations (expected), and verified experimentally in vivo (experimental). The results showed that all bead dosage forms behave in vivo as defined in vitro. Enteric coated beads significantly delay the time to reach the maximum concentration of drug (t_max = 4.9h) compared to uncoated immediate release beads (2h). The lag time of enteric coated beads is 1.1h. CR beads showed both longer t_max (6h) and mean residence time (MRT = 9.7h) compared to the uncoated immediate release beads (t_max = 2h and MRT = 7.1h) as designed in vitro. The in vivo input functions for the three individual beads can be fitted to equations as a function of square root of time. The combined bead dosage form showed t_max of 2.4h and MRT of 7.9h. The experimental and expected in vivo input profiles agreed to within ± 12% (residues at individual data points). Our results suggest that the drug input function of a combined multi‐mechanism oral dosage form can be predicted from the in vivo performance of individual formulations using the dog as an in vivo model.     

Quinoline antimalarials

Quinoline antimalarial patents and relevant scientific literature concerning their mechanism of action, mechanism of resistance and structure-function relationships are discussed in this review. The review provides a brief history of current antimalarial drugs and describes some salient features about their use, occurrence of drug resistance, their metabolism and known adverse effects. Recent advances in our understanding of the mechanism of action of 4-aminoquinolines, quinoline methanols and 8-aminoquinolines are discussed as is the current state of knowledge regarding the mechanisms of drug resistance. New insights into structure-function relationships in 4-aminoquinolines, both with respect to activity and resistance, are emphasised. Finally, patents registered since 1997 are described and an expert opinion offered. The review emphasises advances made during the last four years.     

Antitumor conjugates with polyamine vectors and their molecular mechanisms

Importance of the field: A polyamine conjugate is a special polyamine derivative composed of polyamine vectors appended directly or by a linker to a cargo with specific biological functions. In recent years, extensive researches have emphasized the fact that polyamine conjugates acting as promising antitumor candidates are becoming increasingly important in the polyamine field.

Areas covered in this review: Two key subjects are illustrated in this review. First, various drug-polyamine conjugates and relevant structure–activity relationships are discussed with a focus on the molecular recognition of polyamine transport system (PTS). Second, the design of polyamine conjugates is following a rational mechanism-based strategy. Therefore, it is critically important to understand the intrinsic properties of PTS on the cell membrane, enhanced pharmacological effects of polyamine vector on cellular components, and resulting comprehensive signaling networks.

What the reader will gain: A general design strategy of polyamine conjugates as well as recent progress in both fundamental mechanism studies and preclinical therapies are provided for the readers.

Take home message: The multiple functions of polyamine moieties in objective conjugates furnish broad development space for more efficacious antitumor agents.     

Topical immunomodulators for management of oral mucosal conditions,a systematic review; part I: calcineurin inhibitors

Importance of the field: Topical immunomodulators have been used for the management of oral mucosal diseases. Topical immunomodulating preparations may have utility in local management of oral disease which is resistant to topical steroids and oral findings of an immunologic-mediated systemic disease with primary or persisting, oral mucosal involvement.

Areas covered in this review: This paper is the first part of a systematic review of topical immunomodulators for the management of various oral indications focused on calcineurin inhibitors. The literature search revealed that data are available for cyclosporine, tacrolimus and pimecrolimus. In addition to the review of scientific evidence, this paper presents the potential market, the mechanism of action, the competitive environment and future development options.

What the reader will gain: The reader will find weighted conclusions for the topical use of the calcineurin inhibitors in the management of oral diseases.

Take home message: Topical calcineurin inhibitors may be useful as a second-line treatment in several oral diseases, particularly oral lichen planus.