Advances in systemic delivery of anti-cancer agents for the treatment of metastatic cancer

ABSTRACT

Introduction: The successful treatment of metastatic cancer is refractory to strategies employed to treat confined, primary lesions, such as surgical resection and radiation therapy, and thus must be addressed by systemic delivery of anti-cancer agents. Conventional systemically administered chemotherapeutics are often ineffective and come with severe dose-limiting toxicities.

Areas covered: This review focuses on the recent developments in systemic therapy for metastatic cancer. Firstly, the strategies employed to improve the efficacy of conventional chemotherapeutics by ‘passively’ and ‘actively’ targeting them to tumors are discussed. Secondly, recent advances in the use of biologics to better target cancer and to instigate anti-tumor immunity are reviewed. Under the label of ‘biologics’, antibody-therapies, T cell engaging therapies, oncolytic virotherapies and cell-based therapies are examined and evaluated.

Expert opinion: Improving specificity of action, and engaging the immune system appear to be key goals in the development of novel or reformulated anti-cancer agents for the treatment of metastatic cancer. One of the largest areas of opportunity in this field will be the identification of robust predictive biomarkers for use in conjunction with these agents. Treatment regimens that combine an agent to elicit an immune response (such as an oncolytic virus), and an agent to potentiate/mediate that immune response (such as immune checkpoint inhibitors) are predicted to be more effective than treatment with either agent alone.     

Continuous narcotic infusions for relief of postoperative pain.

Relief of acute pain after surgery or trauma is still inadequate in many centres, most patients being treated with intermittent intramuscular injections of narcotic analgesics. Over the past three years continuous intravenous narcotic infusions have been used at this hospital to treat postoperative pain; recently a system has been devised whereby an hourly dose is given and the dispenser recharged every hour. The method used is cheap and reliable, and signs of overdosage may be easily checked by nursing staff. Side effects rarely occur. Fifty patients who had received intravenous infusions after undergoing major abdominal surgery were sent a questionnaire to assess postoperative pain, and the results were compared with those from 50 matched controls who had received intramuscular injections. Of those who replied, only four patients who had received the infusion had found the pain distressing compared with 13 controls. Continuous narcotic infusions are most effective in relieving postoperative pain and may be given cheaply and reliably.     

New therapeutic strategies in the management of systemic sclerosis

The pathogenic process of systemic sclerosis targets the skin and internal organs, and involves sequential or concomitant abnormalities in blood vessel function, immunity and subsequent fibroblast function. These characteristics are disease specific and may partly explain the unresolved therapeutic strategies that must take into account not only these various biological abnormalities, but also the complexities of the various abnormalities throughout the duration of the disease. However, recent epidemiological data have revealed a decrease in excess mortality, which may be mostly due to the use of cardiovascular drugs. This article deals with present and possible future therapeutic options.     

Contemporaneous management of ampicillin infusions in the outpatient setting through the use of therapeutic drug monitoring

The use of ampicillin in the outpatient setting has traditionally been avoided because of the short half-life and instability in solution of this drug. However, recent in vitro data and two case series support the safe and effective administration of ampicillin by continuous infusion in the community. Therapeutic drug monitoring (TDM) of beta-lactam antibiotics can be used to optimise antibiotic exposure and ensure adequate clinical responses. A case series is presented of patients receiving ampicillin via prolonged infusion in the outpatient setting, with TDM to ensure adequate plasma antibiotic levels were achieved.Three patients who received ampicillin by continuous infusion under the Outpatient Parenteral Antimicrobial Therapy (OPAT) program are described, including details of antibiotic dose and steady-state plasma drug concentration as measured by high-performance liquid chromatography. All three patients had an infection with ampicillin-susceptible Enterococcus faecalis; one patient had post-partum endometritis, one had urosepsis and one had a complex polymicrobial bone and joint infection.Adequate plasma drug levels were achieved in all patients. Management of the antibiotic temperature and infusion times, and appropriate timing of drug levels in the community were required. Two patients achieved clinical cure, while the third required further surgical debridement and antibiotic therapy.TDM in this setting enabled the contemporaneous management and dose alteration of ampicillin. Ampicillin may be a safe and effective drug when administered by continuous infusion with appropriate TDM in the community setting.     

Overuse of intravenous infusions in China: focusing on management platform and cultural problems

This article reviews the current status of the overuse of intravenous (IV) infusions in China and implications to patient safety, and analyzes factors associated with the overuse. Although many factors contribute to the overuse of IV infusions in China, we focus on the construction of an IV infusion management system and tackling cultural problems as the first step to address issues of IV therapy in this commentary.

     

Hippocampal infusions of pyruvate reverse the memory-impairing effects of septal muscimol infusions

Hippocampal infusions of glucose reverse memory deficits in spontaneous alternation and in a continuous multiple trial inhibitory avoidance task. The current experiments tested whether glucose metabolism may participate in these effects of glucose. Specifically, these experiments determined whether the glycolytic metabolite pyruvate would mimic these effects of glucose. Male Sprague–Dawley rats were given septal infusions of vehicle or the gamma-aminobutyric acid (GABA) receptor agonist muscimol (0.15 nmol for spontaneous alternation or 5 nmol for continuous multiple trial inhibitory avoidance) combined with hippocampal infusions of vehicle or pyruvate (200 nmol) 15 min prior to assessing spontaneous alternation or training in a continuous multiple trial inhibitory avoidance task. The infusions of muscimol decreased percent alternation scores and continuous multiple trial inhibitory avoidance retention latencies tested 48 h after training. More importantly, hippocampal infusions of pyruvate reversed the deficits produced by septal infusions of muscimol on both tasks. These findings show for the first time that hippocampal infusions of pyruvate influence memory and suggest that glucose may affect memory via glycolytic metabolism.     

抗疟药物在系统性红斑狼疮中的临床应用

简述了可用于治疗系统性红斑狼疮的3种抗疟药物（氯喹、羟氯喹和阿的平）的药代动力学。作用机制，临床应用及药物不良反应。抗疟药物通过抗炎，免疫抑制，光保护作用，抗血小板聚集及降低血脂等作用，主要应用于轻，中度脏器受累的系统性红斑狼疮，在改善病情，维持病情稳定及预防疾病复发中可发挥重要作用。该类药物安全有效、耐受性良好。     

Benefits of magnesium sulfate in the management of acute human poisoning by organophosphorus insecticides

Organophosphorus chemicals (OPs) are the pesticides most often involved in serious human poisoning. Treatment of intoxication with OPs conventionally involves atropine for reduction of muscarinic signs and oximes that increase the rate of hydrolysis of the phosphorylated enzyme acetylcholinesterase (AChE). Although atropine and oximes (pralidoxime or obidoxime) are traditionally used in the management of such poisoning, their efficacy remains a major issue of debate; thus, the goal of this prospective clinical trial was to elaborate the value of magnesium sulfate (MgSO4) in the management and outcome of OP insecticide poisoning. This unicenter, randomized, single-blind trial study was conducted on patients who were acutely poisoned with OPs and admitted to the Poisoning Center of Loghman-Hakim Hospital in Tehran, Iran. In a systematic sampling, every fourth eligible patient was chosen to undergo MgSO4 treatment. Magnesium sulfate was administered at dose of 4 g/day i.v. continued for only the first 24 hours after admission. The mean daily oxime requirement and the mean daily atropine requirement were not statistically significant between two treated groups. The mortality rate and hospitalization days of patients who received MgSO4 treatment were significantly lower than those who had not received MgSO4 (P < 0.01). It is concluded that administration of MgSO4, in a dose of 4 g/day concurrent to conventional therapy, in OP acute human poisoning is beneficial by reducing the hospitalization days and rate of mortality.     

Basic mechanisms involved in the anti-cancer effects of melatonin

It is commonly accepted that melatonin (N-acetyl-5-methoxytryptamine), the most relevant pineal secretory product, has oncostatic properties in a wide variety of tumors and, especially, in those identified as being hormonedependent. The objective of the present article is to offer a global and integrative view of the mechanisms involved in the oncostatic actions of this indoleamine. Due to the wide spectrum of melatonin's actions, the mechanisms that may be involved in its ability to counteract tumor growth are varied. These include: a) antioxidant effects; b) regulation of the estrogen receptor expression and transactivation; c) modulation of the enzymes involved in the local synthesis of estrogens; d) modulation of cell cycle and induction of apoptosis; e) inhibition of telomerase activity; f) inhibition of metastasis; g) prevention of circadian disruption; h) antiangiogenesis; i) epigenetic effects; j) stimulation of cell differentiation; and k) activation of the immune system. The data supporting each of these oncostatic actions of melatonin are summarized in this review. Moreover, the list of actions described may not be exhaustive in terms of how melatonin modulates tumor growth.     

香豆素类化合物抗肿瘤机制的研究进展

香豆素类化合物是传统的中草药成分,在自然界中普遍存在。近年来,其抗肿瘤作用得到了广泛的关注。研究表明,香豆素类化合物可通过诱导肿瘤细胞凋亡、阻滞细胞分裂周期、抑制肿瘤血管生成及肿瘤细胞迁移和侵袭、抗氧化以及调控多种蛋白和酶的活性等机制发挥抗肿瘤作用。本文综述了近年来香豆素类化合物抗肿瘤机制的研究进展,以期为香豆素类化合物的进一步研究和开发提供理论基础和依据。     

Economic evaluation of the prevention and management of systemic fungal infections in neutropenic patients

Systemic fungal infections in neutropenic patients remain a clinical problem that is associated with morbidity and mortality. Continuing efforts are being made to develop improved (i.e., more effective or safe) drugs, and several new treatments have recently become available. These have increased the therapeutic options available to clinicians to address the problem of systemic fungal infections. Therapeutic choices are difficult when taking into account aspects of efficacy, safety and costs that are associated with the available alternatives. This review summarises the present status of health economic knowledge of the standard therapies that have been available for many years, and also reports on the most recent health economic evidence available for the newly developed treatment alternatives.     

Economic evaluation of the prevention and management of systemic fungal infections in neutropenic patients

Systemic fungal infections in neutropenic patients remain a clinical problem that is associated with morbidity and mortality. Continuing efforts are being made to develop improved (i.e., more effective or safe) drugs, and several new treatments have recently become available. These have increased the therapeutic options available to clinicians to address the problem of systemic fungal infections. Therapeutic choices are difficult when taking into account aspects of efficacy, safety and costs that are associated with the available alternatives. This review summarises the present status of health economic knowledge of the standard therapies that have been available for many years, and also reports on the most recent health economic evidence available for the newly developed treatment alternatives.     

Advances in oral delivery of anti-cancer prodrugs

ABSTRACT

Introduction: Most anticancer drugs have poor aqueous solubility and low permeability across the gastrointestinal tract. Furthermore, extensive efflux by P-glycoproteins (P-gp) in the small intestine also limits the efficient delivery of anticancer drugs via oral route.

Area covered: This review explores the prodrug strategy for oral delivery of anticancer drugs. Different categories of oral anticancer prodrugs along with recent clinical studies have been comprehensively reviewed here. Furthermore, novel anticancer prodrugs such as polymer-prodrugs and lipid-prodrugs have been discussed in detail. Finally, various nanocarrier-based approaches employed for oral delivery of anticancer prodrugs have also been discussed.

Expert opinion: Premature degradation of anticancer prodrugs in the gastrointestinal tract could lead to variable pharmacokinetics and undesired toxicity. Despite their increased aqueous solubility, the oral bioavailability of several anticancer prodrugs are limited by their poor permeability across the gastrointestinal tract. These limitations can be overcome by the use of functional excipients (polymers, lipids, amino acids/dipeptides), which are specifically absorbed via transporters and receptor-mediated endocytosis. Oral delivery of anticancer prodrugs using nanocarrier-based drug delivery system is a recent development; however it should be justified based on the comparative advantages of encapsulating prodrug in a nanocarrier versus the use of anticancer prodrug molecule itself.