Peptide delivery systems

Efficient delivery of peptide drugs to the desired site is very important. There are anumber of barriers that may limit using peptides as potential drugs, some of theseobstacles include poor biomembrane permeability, enzymatic degradation and lowpH. To improve peptide drug efficiency a selective drug delivery system is required.Here we review some of the delivery systems available for peptides and we will alsobriefly discuss peptides that have been used as delivery systems.     

Peptide delivery systems

Summary Efficient delivery of peptide drugs to the desired site is very important. There are a number of barriers that may limit using peptides as potential drugs, some of these obstacles include poor biomembrane permeability, enzymatic degradation and low pH. To improve peptide drug efficiency a selective drug delivery system is required. Here we review some of the delivery systems available for peptides and we will also briefly discuss peptides that have been used as delivery systems.     

Natural product based leads to fight against leishmaniasis

The growing incidence of parasitic resistance against generic pentavalent antimonials, specifically for visceral disease in Indian subcontinent, is a serious issue in Leishmania control. Notwithstanding the two treatment alternatives, that is amphotericin B and miltefosine are being effectively used but their high cost and therapeutic complications limit their use in endemic areas. In the absence of a vaccine candidate, identification, and characterization of novel drugs and targets is a major requirement of leishmanial research. This review describes current drug regimens, putative drug targets, numerous natural products that have shown promising antileishmanial activity alongwith some key issues and strategies for future research to control leishmaniasis worldwide.     

Antifungal Therapeutic Drug Monitoring

A growing body of evidence suggests that patient-to-patient variability in the pharmacokinetics of some antifungals, particularly the mold-active triazoles (itraconazole, voriconazole, and posaconazole) may contribute to therapeutic failure or unexpected toxicity. As a result, many clinicians have recognized a need for therapeutic drug monitoring (TDM) to individualize drug dosing in select patients with suspected or documented invasive fungal infections. However, approaches for performing and interpreting plasma concentrations are not well standardized, and logistical issues such as the turnaround time of test results can limit the clinical usefulness of testing in acutely ill patients. This article summarizes the pharmacologic rationale for TDM of antifungal agents, with a particular focus on recently published data for the newer triazoles, voriconazole and posaconazole. Practical recommendations for TDM-guided dosing are also provided, based on a critical evaluation of literature published over the past 5 years.     

Meeting requirements for primate animals in drug development

An overview on the numbers and species of monkeys used in the area of drug development in the USA and Europe during the years 1975 to 1981 is presented. A marked decline of 25% to 40% in the numbers used is due to a more critical use of the various species, besides a shortage of available animals. However, because for certain experiments some primate species are the animals of choice, there is a limit to further reductions. For future supplies, intensive breeding units, semifree-range colonies, and game farming may be considered. Using the revenue of exported animals, a financial contribution to the conservation of feral animals in the countries of origin could be made.     

Molecular and genetic aspects of resistance to azoles in Candida albicans

Fluconazole is one of the most useful drugs in the treatment of fungal systemic infections which frequently affect non immunocompetent individuals. However, the emergence of resistant strains in recent years may severely limit its usefulness in future. Although there are several described mechanisms involved in resistance to azoles, recent genetic studies demonstrate the role of specific genes in clinical resistance. Currently, the best characterized are the MDR1 and CDR1 genes, which code members of the MFS or ABC family of drug transporters, respectively. These proteins respond to the membrane potential (MFS) or hydrolyse ATP (ABC) thus promoting drug efflux and therefore reducing its intracellular accumulation. It has been shown that the mRNA from these genes is frequently increased in some Candida albicans resistant strains from patients receiving long term azole treatment. The development of molecular genetic tools in C. albicans is allowing characterization of their role in this and other important processes in the fungal cell.     

Effect of intravenous drug administration mode on drug distribution in a tumor slab: a finite Fourier transform analysis

Cancer therapy using chemotherapeutic drugs frequently involves injection of the drug into the body through some intravenous mode of administration, viz, continuous (drip) infusion or single/multiple bolus injection(s). An understanding of the effect of the various modes of administration upon tumor penetration of drug is essential to rational design of drug therapy. This paper investigates drug penetration into a model tumor of slab geometry (between two capillaries) in which the overall transport rate of drug is limited by intra-tumor transport characterized by an effective diffusion coefficient. Employing the method of Finite Fourier Transforms (FFT), analytical solutions have been obtained for transient drug distribution in both the plasma and the tumor following three modes of administration, viz, continuous infusion, single bolus injection and equally-spaced equal-dose multiple bolus injections, of a given amount of drug. The qualitative trends exhibited by the plasma drug distribution profiles are consistent with reported experimental studies. Two concepts, viz, the dimensionless decay constant and the plasma/tumor drug concentration trajectories, are found to be particularly useful in the rational design of drug therapy. The dimensionless decay constant provides a measure of the rate of drug decay in the plasma relative to the rate of drug diffusion into the tumor and is thus characteristic of the tumor/drug system. The magnitude of this parameter dictates the choice of drug administration mode for minimizing drug decay in the plasma while simultaneously maximizing drug transport into the tumor. The concentration trajectories provide a measure of the plasma drug concentration relative to the tumor drug concentration at various times following injection. When the tumor drug concentration exceeds the plasma drug concentration, the drug will begin to diffuse out of the tumor. Knowledge of the time at which this diffusion reversal occurs is especially useful for optimum scheduling of subsequent bolus injections in a multiple bolus dosing regimen. There are no reported applications of the FFT method to solve repeated input functions in either the chemical engineering or pharmaceutical science literature. Thus, the application of FFT method to solve multiple bolus injections is a unique one. Use of this FFT based analysis as a predictor tool can limit the number of costly experiments which are being done now to achieve this purpose. Even though the model in its present form is simplified, the analysis thereof has nevertheless led to a better understanding of the various factors that must be taken into account for rational design of drug therapy.     

一类被开发的HollingⅢ类功能反应模型的定性分析

本文研究了一类捕食种群、食饵种群同时具有收获率的HollingⅢ类功能反应生态系统,其中食饵种群具有非线性密度制约,捕食者无密度制约.应用微分方程定性理论讨论了系统的平衡点,分析了中心焦点的阶数以及稳定性,所给定参数满足一定条件时系统不存在极限环,最后根据细焦点的稳定性判断出极限环的存在性,并验证了极限环的惟一性.     

Prediction of drug combinations by integrating molecular and pharmacological data

Combinatorial therapy is a promising strategy for combating complex disorders due to improved efficacy and reduced side effects. However, screening new drug combinations exhaustively is impractical considering all possible combinations between drugs. Here, we present a novel computational approach to predict drug combinations by integrating molecular and pharmacological data. Specifically, drugs are represented by a set of their properties, such as their targets or indications. By integrating several of these features, we show that feature patterns enriched in approved drug combinations are not only predictive for new drug combinations but also provide insights into mechanisms underlying combinatorial therapy. Further analysis confirmed that among our top ranked predictions of effective combinations, 69% are supported by literature, while the others represent novel potential drug combinations. We believe that our proposed approach can help to limit the search space of drug combinations and provide a new way to effectively utilize existing drugs for new purposes.     

Separation methods for antiviral phosphorus-containing drugs

Among antiviral drugs, phosphorus-containing compounds, foscarnet and cidofovir, present adverse effects including renal toxicity. Since their main therapeutic target is the treatment of CMV retinitis, which needs lifelong maintenance therapy, accurate analytical methods are required for drug monitoring. According to the high hydrophilic property of the two compounds, ion pair reversed-phase HPLC methods were proposed for their separation in drug formulations and biological samples. Their lack of UV absorption at wavelengths above 205 nm does not allow the use of this detection technique for biological fluids. Electrochemical detection methods (coulometry and amperometry) led to a quantification limit of 15 μM for foscarnet. Fluorescent derivatives obtained by modification of cidofovir cytosine nucleus with α-haloketones offered advantage over UV detection and allowed to reach a detection limit of 5 ng/ml, making possible investigations on the drug time-course in biological fluids.     

血小板功能负性调控机制

在血液循环系统中,血小板在抑制因子的作用下,处于静息状态。当机体出血或外界因素刺激时,血小板活化,产生聚集、黏附和释放反应,释放出二磷酸腺苷(ADP)、花生四烯酸(AA)、血小板活化因子和5-羟色胺等物质,招募更多的血小板黏附于出血处,从而启动凝血过程,发挥止血作用。当止血反应完成后,血小板发生解聚,恢复到静息状态。然而,在病理条件下,血小板的内在解聚能力下降,形成过度活化的血小板,产生病理性血栓,导致急性缺血性心血管疾病的发生。临床使用抗血小板药物控制血小板的活化,治疗急性缺血性心血管疾病。然而,目前临床上常用的抗血小板药物发挥抗血小板活化作用的同时,影响了血小板正常的生理性止血作用,产生出血等副作用。因此,我们需要研发新型抗血小板药物,使其既能发挥抗血小板作用,又能减少出血等副作用。本文将对血小板负性调控机制进行综述,为进一步研究抗血小板药物提供思路。     

Modelling antibiotic- and anti-quorum sensing treatment of a spatially-structured Pseudomonas aeruginosa population

The bacterial cell to cell signalling system known as quorum sensing (QS) is essential for the regulation of virulence in many pathogens and offers a specific biochemical target for novel antibacterial therapies. Expanding on earlier work, in which consideration was given to the primary QS system (lasR system) in a homogeneous population of the common human pathogen Pseudomonas aeruginosa, we build a simple spatial model of an early-stage P. aeruginosa biofilm subject to treatment with topically applied anti-QS drugs (of two specific kinds) and conventional antibiotics. In the case of a slowly growing biofilm we show that both kinds of anti-quorum sensing drug are effective in reducing the level of the relevant signal molecule (3-oxo-C12-homoserine lactone; henceforth AHL), in each case obtaining an explicit bound on the steady-state AHL profile in terms of a prescribed surface drug concentration. Using numerical methods, we are also able to reproduce the hysteretic phenomena exhibited by the homogeneous model, in particular showing that for each kind of anti-QS drug there is a parameter regime in which a catastrophic collapse occurs in the steady-state AHL concentration as the surface drug concentration passes some critical value; an alternative way of interpreting this result is to say that, for a prescribed surface drug concentration, there is a critical biofilm depth such that treatment is successful until this depth is reached, but fails thereafter. In the thick-biofilm limit we show that the critical concentration of each drug increases exponentially with the biofilm thickness (or, conversely, that the critical depth increases logarithmically with surface drug concentration); this is dramatically different to the behaviour observed in the corresponding homogeneous model, where the critical concentrations grow linearly with bacterial carrying capacity, and thus highlights the relative difficulty of treating a large, spatially-structured population with diffusing antibacterials.     

Cholinesterase Inhibitors Stabilize Alzheimer Disease

During the last decade, a systematic effort to develop a pharmacological treatment for Alzheimer disease (AD) has resulted into three drugs being registered for the first time in USA and Europe for this specific indication. All three are cholinesterase inhibitors (ChEI). The major therapeutic effect of ChEI on AD patients is to maintain cognitive function at a constant level during a 6 months to one year period of treatment as compared to placebo. Additional drug effects might be slowing cognitive deterioration and improving behavioral and daily living conditions. Comparison of clinical effects of 6 ChEI demonstrates a rather similar magnitude of improvement in cognitive measures. For some drugs. this may represent an upper limit while for other it may still be possible to increase further the benefit. In order to maximize and prolong positive drug effects it is important to start early and adjust dosage during the treatment. Recent studies show that in many patients the stabilization effect produced by ChEI can be prolonged for as long as a 24 month period. In order to explain the stabilizing effect of ChEI, a mechanism other than AChE inhibition, based on beta-amyloid metabolism, is postulated.     

Numerical simulation of iontophoresis in the drug delivery system

The architecture and composition of stratum corneum act as barriers and limit the diffusion of most drug molecules and ions. Much effort has been made to overcome this barrier and it can be seen that iontophoresis has shown a good effect. Iontophoresis represents the application of low electrical potential to increase the transport of drugs into and across the skin or tissue. Iontophoresis is a noninvasive drug delivery system, and therefore, it is a useful alternative to drug transportation by injection. In this study, we present a numerical model and effects of electrical potential on the drug diffusion in the buccal tissue and the stratum corneum. The initial numerical results are in good comparison with experimental observation. We demonstrate that the application of an applied voltage can greatly improve the efficacy of localized drug delivery as compared to diffusion alone.     

Enzyme-triggered nanomedicine: drug release strategies in cancer therapy

Nanomedicine as a field has emerged from the early success of nanoparticle-based drug delivery systems, in particular for treatment of cancer, and the advances made in nano- and biotechnology over the past decade. A prerequisite for nanoparticle-based drug delivery systems to be effective is that the drug payload is released at the target site. A large number of drug release strategies have been proposed that can be classified into certain areas. The simplest and most successful strategy so far, probably due to relative simplicity, is based on utilizing certain physico-chemical characteristics of drugs to obtain a slow drug leakage from the formulations after accumulation in the cancerous site. However, this strategy is only applicable to a relatively small range of drugs and cannot be applied to biologicals. Many advanced drug release strategies have therefore been investigated. Such strategies include utilization of heat, light and ultrasound sensitive systems and in particular pH sensitive systems where the lower pH in endosomes induces drug release. Highly interesting are enzyme sensitive systems where over-expressed disease-associated enzymes are utilized to trigger drug release. The enzyme-based strategies are particularly interesting as they require no prior knowledge of the tumour localization. The basis of this review is an evaluation of the current status of drug delivery strategies focused on triggered drug release by disease-associated enzymes. We limit ourselves to reviewing the liposome field, but the concepts and conclusions are equally important for polymer-based systems.     

Drug resistance in brain diseases and the role of drug efflux transporters

Resistance to drug treatment is an important hurdle in the therapy of many brain disorders, including brain cancer, epilepsy, schizophrenia, depression and infection of the brain with HIV. Consequently, there is a pressing need to develop new and more effective treatment strategies. Mechanisms of resistance that operate in cancer and infectious diseases might also be relevant in drug-resistant brain disorders. In particular, drug efflux transporters that are expressed at the blood-brain barrier limit the ability of many drugs to access the brain. There is increasing evidence that drug efflux transporters have an important role in drug-resistant brain disorders, and this information should allow more efficacious treatment strategies to be developed.     

Astroglial Knockout of Glucocorticoid Receptor Attenuates Morphine Withdrawal Symptoms,but Not Antinociception and Tolerance in Mice

The development of tolerance and drug dependence limit the clinical application of opioids for the treatment of severe pain. Glucocorticoid receptors (GRs) are among molecular substrates involved in these processes. Most studies focus on the role of neuronal GR, while the involvement of GR on glial cells is not fully understood. To address this issue, we used a transgenic model of conditional GR knockout mice, targeted to connexin 30-expressing astrocytes, treated with repeated doses of morphine. We observed no difference between control mice and astrocytic GR knockouts in the development of antinociceptive tolerance. Nevertheless, when animals were subjected to precipitated withdrawal, knockouts presented some attenuated symptoms, including jumping. Taken together, our data suggest that hippocampal and spinal astrocytic GRs appear to be involved in opioid withdrawal, and drugs targeting the GR may relieve some symptoms of morphine withdrawal without influencing its antinociceptive properties.

     

Application of silver nanoparticles to the chemiluminescence determination of cefditoren pivoxil using the luminol–ferricyanide system

A new simple, accurate and sensitive sequential injection analysis chemiluminescence (CL) detection method for the determination of cefditoren pivoxil (CTP) has been developed. The developed method was based on the enhancement effect of silver nanoparticles on the CL signal arising from a luminol–potassium ferricyanide reaction in the presence of CTP. The optimum conditions relevant to the effect of luminol, potassium ferricyanide and silver nanoparticle concentrations were investigated. The proposed method showed linear relationships between relative CL intensity and the investigated drug concentration at the range 0.001–5000 ng/mL, (r = 0.9998, n = 12) with a detection limit of 0.5 pg/mL and quantification limit of 0.001 ng/mL. The relative standard deviation was 1.6%. The proposed method was employed for the determination of CTP in bulk drug, in its pharmaceutical dosage forms and biological fluids such as human serum and urine. The interference of some common additive compounds such as glucose, lactose, starch, talc and magnesium stearate was investigated. In addition, the interference of some related cephalosporins was tested. No interference was recorded. The obtained sequential injection analysis‐CL results were statistically compared with those from a reported method and did not show any significant differences. Copyright © 2014 John Wiley & Sons, Ltd.     

Cycle-time and residence-time density approximations in a stochastic model for circulatory transport

The concentration of a drug in the circulatory system is studied under two different elimination strategies. The first strategy—geometric elimination—is the classical one which assumes a constant elimination rate per cycle. The second strategy—Poisson elimination—assumes that the elimination rate changes during the process of elimination. The problem studied here is to find a relationship between the residence-time distribution and the cycle-time distribution for a given rule of elimination. While the presented model gives this relationship in terms of Laplace-Stieltjes transform, the aim here is to determine the shapes of the corresponding probability density functions. From experimental data, we expect positively skewed, gamma-like distributions for the residence time of the drug in the body. Also, as some elimination parameter in the model approaches a limit, the exponential distribution often arises. Therefore, we use laguerre series expansions, which yield a parsimonious approximation of positively skewed probability densities that are close to a gamma distribution. The coefficients in the expansion are determined by the central moments, which can be obtained from experimental data or as a consequence of theoretical assumptions. The examples presented show that gamma-like densities arise for a diverse set of cycle-time distributions and under both elimination rules.