Nanoparticle-based drug delivery systems: a commercial and regulatory outlook as the field matures

Introduction: Nanomedicine has emerged as a major field of academic research with direct impact on human health. While a first generation of products has been successfully commercialized and has significantly contributed to enhance patient’s life, recent advances in material design and the emergence of new therapeutics are contributing to the development of more sophisticated systems. As the field matures, it is important to comprehend the challenges related to nanoparticle commercial development for a more efficient and predictable path to the clinic.

Areas covered: The review provides an overview of nanoparticle-based delivery systems currently on the market and in clinical trials, and discuss the principal challenges for their commercial development, both from a manufacturing and regulatory perspective, to help gain understanding of the translational path for these systems.

Expert opinion: Clinical translation of nanoparticle-based delivery systems remains challenging on account of their 3D nanostructure and requires robust nano-manufacturing process along with adequate analytical tools and methodologies. By identifying early enough in the development the product critical attributes and understanding their impact on the therapeutic performance, the developers of nanopharmaceuticals will be better equipped to develop efficient product pipelines. Second-generation products are expected to broaden nanopharmaceutical global market in the upcoming years.     

Advancements in the treatment of hypothyroidism with L-T4 liquid formulation or soft gel capsule: an update

Introduction: The most recent advance concerning levothyroxine (L-T4) therapy is the development of novel oral formulations: the liquid preparation, and the soft gel capsule.

Areas covered: This review evaluates the most recent clinical studies about these new formulations. The liquid formulation has been shown to overcome: the food and beverages intereference with L-T4 tablets absorption, caused by food or coffee at breakfast; malabsorption induced by the increased gastric pH, resulting from atrophic gastritis, or due to proton-pump inhibitors; and malabsorption after bariatric surgery. The use of liquid L-T4 has been studied also in pregnancy, newborns and infants, suggesting a better bioequivalence than tablets. Finally, liquid L-T4 is more active than tablets in the control of thyroid-stimulating hormone (TSH) in hypothyroid patients without malabsorption, drug interference, or gastric disorders, leading to a hypothesized higher absorption of liquid L-T4 also in these patients. Few studies have evaluated soft gel L-T4 with promising results in patients with malabsorption related to coffee or gastritis.

Expert opinion: Liquid L-T4 (and soft gel capsules) are more active than the tablet L-T4 in the control of TSH in hypothyroid patients with gastric disorders, malabsorption, or drug interference, but also in patients without absorption disorders.     

Combating mutations in genetic disease and drug resistance: understanding molecular mechanisms to guide drug design

Introduction: Mutations introduce diversity into genomes, leading to selective changes and driving evolution. These changes have contributed to the emergence of many of the current major health concerns of the 21st century, from the development of genetic diseases and cancers to the rise and spread of drug resistance. The experimental systematic testing of all mutations in a system of interest is impractical and not cost-effective, which has created interest in the development of computational tools to understand the molecular consequences of mutations to aid and guide rational experimentation.

Areas covered: Here, the authors discuss the recent development of computational methods to understand the effects of coding mutations to protein function and interactions, particularly in the context of the 3D structure of the protein.

Expert opinion: While significant progress has been made in terms of innovative tools to understand and quantify the different range of effects in which a mutation or a set of mutations can give rise to a phenotype, a great gap still exists when integrating these predictions and drawing causality conclusions linking variants. This often requires a detailed understanding of the system being perturbed. However, as part of the drug development process it can be used preemptively in a similar fashion to pharmacokinetics predictions, to guide development of therapeutics to help guide the design and analysis of clinical trials, patient treatment and public health policy strategies.     

New strategies against drug resistance to herpes simplex virus

Herpes simplex virus (HSV), a member of the Herpesviridae family, is a significant human pathogen that results in mucocutaneous lesions in the oral cavity or genital infections. Acyclovir (ACV) and related nucleoside analogues can successfully treat HSV infections, but the emergence of drug resistance to ACV has created a barrier for the treatment of HSV infections, especially in immunocompromised patients. There is an urgent need to explore new and effective tactics to circumvent drug resistance to HSV. This review summarises the current strategies in the development of new targets (the DNA helicase/primase (H/P) complex), new types of molecules (nature products) and new antiviral mechanisms (lethal mutagenesis of Janus-type nucleosides) to fight the drug resistance of HSV.     

Persistent systemic monocyte and neutrophil activation in neonatal encephalopathy

Aim: Circulating immune cell activation is associated with worse outcome in adult and animal models of brain injury. Our aim was to profile the systemic inflammatory response over the first week of life in infants at risk of neonatal encephalopathy (NE) and correlate early neutrophil and monocyte endotoxin and activation responses with outcome.

Methods: Prospective observational study in a tertiary referral university hospital including 22 infants requiring resuscitation at birth who had serial (five time points) neutrophil and monocyte CD11b (marker of cell adhesion), intracellular reactive oxygen intermediates (ROI; cell activation) and Toll-like receptor (TLR; endotoxin recognition) before and after endotoxin stimulation ex vivo compared to neonatal controls.

Results: All neonates requiring resuscitation at delivery (n?=?122 samples) had higher neutrophil and monocyte CD11b and TLR-4 expression compared with adults and neonatal controls. Neonates with abnormal neuroimaging and/or severe NE had increased CD11b, ROI and TLR-4. Increased polymorphonuclear leukocytes TLR-4 expression was associated with increased mortality in infants with NE.

Conclusion: Innate immune dysregulation in the first week of life is associated with severity of outcome in neonatal brain injury in this cohort and may be amenable to immunomodulation.     

儿童沙门菌感染临床特点及耐药模式

目的了解儿童沙门菌感染的流行特征和耐药模式。方法分析2012年2月—2014年9月住院且粪便细菌培养出沙门菌菌株患儿的临床特点,以及沙门菌的血清型和药敏试验结果。结果从2 678例住院患儿粪便标本中检测出87株沙门菌,5—9月份共检测出64株(73.56%)。87例沙门菌阳性患儿中,男58例、女29例,其中2岁的68例(78.16%)。临床症状主要为脓血便65例(74.71%),发热72例(82.76%)。合并有轮状病毒感染10例(11.49%)。经沙门菌血清学鉴定,分别为布利丹沙门菌6株,肠炎沙门菌6株,鼠伤寒沙门菌5株,亚利桑那沙门菌3株,奥拉宁堡沙门菌2株,策维埃沙门菌2株,纽兰芝沙门菌、德比沙门菌、阿哥纳沙门菌、布伦登芦普沙门菌、埃可沙门菌各1株。药敏试验结果显示,沙门菌对头孢唑啉、头孢呋辛、庆大霉素的耐药率分别为94.25%、87.36%、87.36%,有26株(29.89%)沙门菌呈多重耐药。结论 2岁儿童沙门菌易感,男性患儿居多,主要表现为脓血便、发热,有部分合并轮状病毒感染;沙门菌血清型以布利丹沙门菌、肠炎沙门菌和鼠伤寒沙门菌多见,对多种抗生素耐药,甚至多重耐药。     

Stress Mediates the Relationship Between Past Drug Addiction and Current Risky Sexual Behaviour Among Low‐income Women

This study examined the role of stress as a mediator of the relationship between prior drug addiction and current high‐risk sexual behaviour. Eight hundred twenty women aged 18 to 30 years, who received care at community‐based family planning clinics, were interviewed using the Composite International Diagnostic Interview and the Sexual Risk Behavior Assessment Schedule. They also completed the brief version of the Self‐Control Scale as a measure of problem‐solving strategies and measures of recent stressful events, daily hassles and ongoing chronic stress. Regardless of addiction history, stress exposure during the previous 12 months was associated with risky sexual behaviour during the previous 12 months. Structural equation modelling revealed that 12‐month stress levels mediated the relationship between past drug addiction and 12‐month high‐risk sexual behaviours, as well as the negative relationship between problem‐solving strategies and high‐risk sexual behaviours. Problem‐solving strategies did not moderate the relationship between drug addiction and high‐risk sexual behaviours. These findings suggest that stress management training may help reduce risky behaviour among young, low‐income women Copyright © 2014 John Wiley & Sons, Ltd.     

脑源性神经生长因子对首发精神分裂症患者早期改善的预测作用

目的探讨血清脑源性神经生长因子（BDNF）对首发精神分裂症患者早期改善的预测作用。方法选择90例女性首发精神分裂症患者为研究对象,给予利培酮治疗8周。在治疗前,治疗第2、8周末检测血清BDNF水平;采用阳性与阴性症状量表（PANSS）评定疗效,根据2周末PANSS减分率分为早期改善组51例（≥20%）和非早期改善组39例（＜20%）。选择同期45例女性健康者为正常对照组,检测其血清BDNF水平,与精神分裂症患者进行比较分析。结果与正常对照组比较,早期改善组治疗前、治疗第2周末血清BDNF水平均明显较低（均P＜0.01）,治疗第8周末差异无统计学意义（P＞0.05）;与非早期改善组比较,治疗前,治疗第2、8周末血清BDNF水平均明显较高（均P＜0.05）。非早期改善组治疗前,治疗第2、8周末血清BDNF水平均明显低于正常对照组（均P＜0.01）。与自身治疗前比较,早期改善组和非早期改善组第2、8周末血清BDNF水平均明显升高（均P＜0.05）。经logistic回归分析,治疗前血清BDNF水平是治疗2周末早期改善的影响因素。治疗第8周末早期改善组治疗有效率为80.4%,明显高于非早期改善组的59.0%（P＜0.05）。结论首发精神分裂症患者存在BDNF异常降低,但经抗精神病药物治疗后明显改善,且治疗前BDNF水平对早期改善具有一定的预测作用。     

Rats exposed to cocaine during late gestation and early postnatal life show deficits in hippocampal pyramidal and granule cells in later life

In humans, the offspring of maternal cocaine misusers are known to have subtle cognitive and motor impairments in later life. It was therefore hypothesized that such exposure in animals would also affect the morphological structure of the brain. This possibility was investigated by exposing rats to cocaine between embryonic day 15 and postnatal day 6. Samples of the cocaine-exposed and control rats were killed for examination at 22 and 150 postnatal days of age. Stereological procedures (the Cavalieri principle together with the physical disector method) were utilized to estimate the total number of pyramidal and granule cells in defined regions of the hippocampal formation. At 22 days of age, the control offspring had about 373 000 pyramidal cells whereas the cocaine-treated animals only had about 310,000 cells in the CA1 + CA2 + CA3 region. By 150 days of age the values were about 396,000 and 348,000, respectively. The differences between age-matched groups were statistically significant. There were about 626,000 and 687,000 dentate gyrus granule cells in the 22-day-old control and cocaine-treated groups, respectively. By postnatal day 150 the control rats had about 832,000 granule cells whilst the cocaine-treated rats had about 693,000. There was a significant main effect of age as well as group-age interaction in this measure. These results show that even moderate exposure to cocaine during the late gestation and early postnatal period in rats is a potent teratogen and can markedly influence the development of neurons in the hippocampal formation.