Therapeutic strategies for invasive fungal infections in neonatal and pediatric patients

Invasive Candida and Aspergillus infections are the most commonly encountered fungal infections. They appear to be life threatening in the setting of profound immunosuppression, whereas cases that are resistant to antifungal therapy are occasionally encountered. Novel antifungal triazole and echinocandin agents appear to exhibit good activity as first-line or salvage therapy, whereas the use of amphotericin B formulations is particularly valuable in neonates. Significant differences in toxicity have been demonstrated among various antifungal agents with in vitro activity from available comparative data on fungal infections in children: however, no clear difference in treatment efficacy has been demonstrated. However, very little data are available about neonates. Host factors and responsible fungal species most frequently guide the choice of therapy.     

Itraconazole: An update on pharmacology and clinical use for treatment of invasive and allergic fungal infections

解决伊曲康唑的难溶性问题,提高其体外溶出度,为伊曲康唑多颗粒体系进一步工业化放大生产提供参考。

采用流化床底喷包衣工艺,制备伊曲康唑多颗粒体系微丸,将伊曲康唑与羟丙甲纤维素溶于有机溶剂后喷载于蔗糖丸芯表面,在微丸表面形成固体分散体。采用单因素法考察流化床底喷包衣制备参数。采用星点设计-响应面法,以累积溶出度、上药效率及黏连率为响应值,对伊曲康唑多颗粒体系的药物载体质量比和丸芯增重进行优化。制备样品对优化后处方进行验证,通过扫描电子显微镜观察伊曲康唑多颗粒体系的镜下层级结构,运用差示扫描量热法(differential scanning calorimetry ,DSC)及X-射线粉末衍射法(X-ray diffraction,XRD)对伊曲康唑多颗粒体系微丸中的固体分散体进行表征,并通过对比伊曲康唑微丸和物理混合物在0.1 mol·L⁻¹ HCl溶出介质中的溶出曲线,对其增溶效果进行验证。

单因素法确定流化床底喷包衣参数,泵液速度为3.0~5.0 mL·min⁻¹,雾化压力为1.5 bar,进风量为110 m³·h⁻¹,物料温度为35 ℃;根据星点设计-响应面法拟合优化后处方的药物载体质量比为1∶1.5,丸芯增重为75%,此时各响应值达到期望值。根据扫描电子显微镜结果可知伊曲康唑多颗粒体系微丸直径约为910 µm,微丸的蔗糖丸芯直径约为570 µm,上药后载药层厚度约为110 µm,包封层厚度约为11 µm。通过DSC与XRD结果可知伊曲康唑多颗粒体系微丸中伊曲康唑形成了均匀的固体分散体,为无定形。在0.1 mol·L⁻¹ HCl溶出介质中,第90分钟多颗粒体系累积溶出度约为物理混合物的10倍,增溶效果显著。

将伊曲康唑制成多颗粒体系微丸,形成固体分散体,可以显著改善伊曲康唑的体外溶出度。

     

13th Annual Meeting of the Safety Pharmacology Society: focus on novel technologies and safety pharmacology frontiers

Introduction: The 13th Annual Meeting of the Safety Pharmacology (SP) Society discussed novel therapeutic areas, recent regulatory developments, emerging biology technologies and non-pharmaceutical dairy products that may need SP evaluations for ensuring their human safety.

Areas covered: The meeting honored Willem Einthoven, the father of electrocardiography. The Comprehensive in vitro Proarrhythmia Assay (CiPA) is an under-discussion proposal for replacing the International Conference on Hamonization (ICH) S7B guideline strategy. Drugs targeting epigenetic mechanisms (e.g., histone deacetylase inhibitors) have the potential to produce proarrhythmic safety liabilities by dysregulating the synthesis of cardiac ion channel proteins as well as the intracellular machinery, moving them to sarcolemmal residence. Novel frontiers of regulatory SP investigations are functional food and probiotic (microorganisms) preparations.

Expert opinion: The CiPA initiative is a unique opportunity for concerned stakeholders to drive SP into the adoption of 21st century safety assessment platforms, which, for discovering and mitigating mechanisms conferring safety risks to drugs, apply chiefly in silico and in vitro rather than traditional in vivo pharmacodynamics assays. The SP evaluation of functional foods and probiotics needs the development of product-tailored investigational approaches.     

Discovery and therapeutic potential of kinin receptor antagonists

Introduction: Kinins are bioactive peptide hormones that exert biological effects by activating two types of G protein-coupled receptors namely, B₁ (B₁R) and B₂ (B₂R). These modulate normal physiological cellular functions, inflammatory disorders and carcinogenesis. New and novel kinin receptor antagonists have been synthesized and their efficacy evaluated.

Areas covered: The authors provide a comprehensive review on the cellular and molecular biology of kinins and their receptors is delineated along with evolution and discovery of selective peptide and non-peptide antagonists. The authors describe the in vitro and in vivo methods used to understand the relative functional roles of B₁R and B₂R in physiology and pathohysiology. Furthermore, the authors translate the evaluation of kinin antagonists in selected preclinical models and associated clinical indications. Literature was surveyed from original publications, standard sources, SciFinder, patent applications and clinical trials.

Expert opinion: The authors suggest that several key areas of functional biology need consideration, namely: re-evaluation, particularly in vivo, of the mechanism of action and relative functional roles of the B₁R and B₂R in physiology and acute and chronic disease in animals and man; need for improved animal models with increased use of humanized and human systems; development of fluorescent probes for use in vivo in animals and man using advanced imaging techniques; combination of kinin receptor antagonists and traditional chemotherapy for various cancers.     

Plasma-derived human factor X concentrate for on-demand and perioperative treatment in factor X-deficient patients: pharmacology,pharmacokinetics, efficacy,and safety

Introduction: Hereditary factor X (FX) deficiency is a rare autosomal recessive bleeding disorder characterized mainly by mild-to-severe bleeding into the mucous membranes, muscles or joints. Previously, treatment options for hereditary FX deficiency were limited mostly to products that may not specify FX content (i.e. fresh frozen plasma and prothrombin complex concentrates) and that have associated safety concerns. To meet the need for a single-factor replacement therapy specifically for use in FX-deficient patients, a high-purity, high-potency, human plasma-derived FX concentrate (pdFX; Coagadex®; Bio Products Laboratory, Elstree, UK) has been developed and approved for treatment of perioperative bleeding and on-demand treatment in FX-deficient patients.

Areas covered: The pharmacology, efficacy, and safety of pdFX are discussed, with a review of preclinical studies and clinical trial data that led to regulatory approval of pdFX in the United States and Europe.

Expert opinion: As the first single-factor replacement therapy indicated for hereditary FX deficiency, pdFX is a safe and efficacious treatment option in patients aged ≥12 years with hereditary FX deficiency. Clinical studies of pdFX provide a dosing regimen for use in cases of bleeding episodes, surgery, and prophylaxis. Further studies are ongoing regarding use of pdFX long term and in patients aged ≤12 years.     

Food additive carrageenan: Part I: A critical review of carrageenan in vitro studies,potential pitfalls,and implications for human health and safety

Carrageenan (CGN) has been used as a safe food additive for several decades. Confusion over nomenclature, basic CGN chemistry, type of CGN tested, interspecies biology, and misinterpretation of both in vivo and in vitro data has resulted in the dissemination of incorrect information regarding the human safety of CGN. The issue is exacerbated when mechanistic data obtained from in vitro experiments are directly translated to human hazard and used for risk assessment. This can lead to information that is taken out of experimental context and reported as a definitive effect in humans. In recent years, the use of cell-based models has increased and their ability to provide key information regarding chemical or drug safety is well established. In many instances, these new alternative approaches have started to replace the need to use animals altogether. In vitro systems can be extremely useful for understanding subcellular targets and mechanisms of adverse effects. However, care must be exercised when extrapolating the in vitro findings to in vivo effects. Often, issues such as chemical identity and purity, relevant dose, pharmacokinetic properties, solubility, protein binding, adsorption to plastics, and the use of cell models that are biologically and mechanistically relevant are overlooked or ignored. When this occurs, in vitro findings can provide misleading information that is not causally linked to in vivo events in animals or in humans. To date, there has not been a comprehensive review of the CGN in vitro literature, which has reported a wide range of biochemical effects related to this compound. An extensive effort has been made to evaluate as much of this literature as possible. This review focuses on the in vitro observation, the unique chemistry of CGN, and potential pitfalls of in vitro models used for hazard identification. The discussion of the in vitro studies discussed this review are supported by numerous in vivo studies. This provides a unique opportunity to have both the in vitro and in vivo studies reviewed together.     

Drug‐drug interaction and doping,part 2: An in vitro study on the effect of non‐prohibited drugs on the phase I metabolic profile of stanozolol

The present study was designed to provide preliminary information on the potential impact of metabolic drug‐drug interaction on the effectiveness of doping control strategies currently followed by the anti‐doping laboratories to detect the intake of prohibited agents. In vitro assays based on the use of human liver microsomes and recombinant cytochrome P450 isoforms were developed and applied to characterize the phase I metabolic profile of the prohibited agent stanozolol, both in the absence and in the presence of substances (ketoconazole, itraconazole, miconazole, cimetidine, ranitidine, and nefazodone) not included in the World Anti‐Doping Agency (WADA) list of prohibited substances and methods and frequently administered to athletes. The results show that the in vitro model utilized in this study is adequate to simulate the in vivo metabolism of stanozolol. Furthermore, our data showed that ketoconazole, itraconazole, miconazole, and nefazodone caused a marked modification in the production of the metabolic products (3’‐hydroxy‐stanozolol, 4β‐hydroxy‐stanozolol and 16β‐hydroxy‐stanozolol) normally selected by the anti‐doping laboratories as target analytes to detect stanozolol intake. On the contrary, moderate variations were registered in the presence of cimetidine and no significant modifications were measured in the presence of ranitidine. This evidence confirms that the potential effect of drug‐drug interactions is duly taken into account also in anti‐doping analysis. Copyright © 2014 John Wiley & Sons, Ltd.     

Drug‐drug interaction and doping,part 1: An in vitro study on the effect of non‐prohibited drugs on the phase I metabolic profile of toremifene

The present study was designed to provide preliminary information on the potential impact of metabolic drug‐drug interaction on the effectiveness of doping control strategies currently followed by the anti‐doping laboratories to detect the intake of banned agents. In vitro assays based on the use of human liver microsomes and recombinant CYP isoforms were designed and performed to characterize the phase I metabolic profile of the prohibited agent toremifene, selected as a prototype drug of the class of selective oestrogen receptor modulators, both in the absence and in the presence of medicaments (fluconazole, ketoconazole, itraconazole, miconazole, cimetidine, ranitidine, fluoxetine, paroxetine, nefazodone) not included in the World Anti‐Doping Agency list of prohibited substances and methods and frequently administered to athletes. The results show that the in vitro model developed in this study was adequate to simulate the in vivo metabolism of toremifene, confirming the results obtained in previous studies. Furthermore, our data also show that ketoconazole, itraconazole, miconazole and nefazodone cause a marked modification in the production of the metabolic products (i.e. hydroxylated and carboxylated metabolites) normally selected by the anti‐doping laboratories as target analytes to detect toremifene intake; moderate variations were registered in the presence of fluconazole, paroxetine and fluoxetine; while no significant modifications were measured in the presence of ranitidine and cimetidine. This evidence imposes that the potential effect of drug‐drug interactions is duly taken into account in anti‐doping analysis, also for a broader significance of the analytical results. Copyright © 2014 John Wiley & Sons, Ltd.