Stefan Mühlebach

ESPEN Guidelines on Parenteral Nutrition: Home Parenteral Nutrition (HPN) in adult patients

Home parenteral nutrition (HPN) was introduced as a treatment modality in the early 1970s primarily for the treatment of chronic intestinal failure in patients with benign disease. The relatively low morbidity and mortality associated with HPN has encouraged its widespread use in western countries. Thus there is huge clinical experience, but there are still few controlled clinical studies of treatment effects and management of complications. The purpose of these guidelines is to highlight areas of good practice and promote the use of standardized treatment protocols between centers. The guidelines may serve as a framework for development of policies and procedures.

ESPEN guidelines on nutrition in cancer patients

Cancers are among the leading causes of morbidity and mortality worldwide, and the number of new cases is expected to rise significantly over the next decades. At the same time, all types of cancer treatment, such as surgery, radiation therapy, and pharmacological therapies are improving in sophistication, precision and in the power to target specific characteristics of individual cancers. Thus, while many cancers may still not be cured they may be converted to chronic diseases. All of these treatments, however, are impeded or precluded by the frequent development of malnutrition and metabolic derangements in cancer patients, induced by the tumor or by its treatment. These evidence-based guidelines were developed to translate current best evidence and expert opinion into recommendations for multi-disciplinary teams responsible for identification, prevention, and treatment of reversible elements of malnutrition in adult cancer patients. The guidelines were commissioned and financially supported by ESPEN and by the European Partnership for Action Against Cancer (EPAAC), an EU level initiative. Members of the guideline group were selected by ESPEN to include a range of professions and fields of expertise. We searched for meta-analyses, systematic reviews and comparative studies based on clinical questions according to the PICO format. The evidence was evaluated and merged to develop clinical recommendations using the GRADE method. Due to the deficits in the available evidence, relevant still open questions were listed and should be addressed by future studies. Malnutrition and a loss of muscle mass are frequent in cancer patients and have a negative effect on clinical outcome. They may be driven by inadequate food intake, decreased physical activity and catabolic metabolic derangements. To screen for, prevent, assess in detail, monitor and treat malnutrition standard operating procedures, responsibilities and a quality control process should be established at each institution involved in treating cancer patients. All cancer patients should be screened regularly for the risk or the presence of malnutrition. In all patients - with the exception of end of life care - energy and substrate requirements should be met by offering in a step-wise manner nutritional interventions from counseling to parenteral nutrition. However, benefits and risks of nutritional interventions have to be balanced with special consideration in patients with advanced disease. Nutritional care should always be accompanied by exercise training. To counter malnutrition in patients with advanced cancer there are few pharmacological agents and pharmaconutrients with only limited effects. Cancer survivors should engage in regular physical activity and adopt a prudent diet.

Nutritional risk is a clinical predictor of postoperative mortality and morbidity in surgery for colorectal cancer.

This study investigated whether nutritional risk scores applied at hospital admission predict mortality and complications after colorectal cancer surgery.

Nanomedicines: addressing the scientific and regulatory gap.

Nanomedicine is the application of nanotechnology to the discipline of medicine: the use of nanoscale materials for the diagnosis, monitoring, control, prevention, and treatment of disease. Nanomedicine holds tremendous promise to revolutionize medicine across disciplines and specialties, but this promise has yet to be fully realized. Beyond the typical complications associated with drug development, the fundamentally different and novel physical and chemical properties of some nanomaterials compared to materials on a larger scale (i.e., their bulk counterparts) can create a unique set of opportunities as well as safety concerns, which have only begun to be explored. As the research community continues to investigate nanomedicines, their efficacy, and the associated safety issues, it is critical to work to close the scientific and regulatory gaps to assure that nanomedicine drives the next generation of biomedical innovation.

How to regulate nonbiological complex drugs (NBCD) and their follow-on versions: points to consider.

The aim of this critical review is to reach a global consensus regarding the introduction of follow-on versions of nonbiological complex drugs (NBCD). A nonbiological complex drug is a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that cannot be isolated and fully quantitated, characterized and/or described by state of the art physicochemical analytical means and where the clinical meaning of the differences is not known. The composition, quality and in vivo performance of NBCD are highly dependent on manufacturing processes of both the active ingredient as well as in most cases the formulation. The challenges posed by the development of follow-on versions of NBCD are illustrated in this paper by discussing the ‘families’ of liposomes, iron–carbohydrate (‘iron–sugar’) drugs and glatiramoids. It is proposed that the same principles for the marketing authorization of copies of NBCD as for biosimilars be used: the need for animal and/or clinical data and the need to show similarity in quality, safety and efficacy. The regulatory approach of NBCD will have to take into consideration the specific characteristics of the drugs, their formulation and manufacturing process and the resulting critical attributes to achieve their desired quality, safety and efficacy. As with the biosimilars, for the NBCD product, family-specific methods should be evaluated and applied where scientifically proven, including sophisticated quality methods, pharmacodynamic markers and animal models. Concerning substitution and interchangeability of NBCD, it is also advisable to take biosimilars as an example, i.e. (1) substitution without the involvement of a healthcare professional should be discouraged to ensure traceability of the treatment of individual patients, (2) keep an individual patient on a specific treatment if the patient is doing well and only switch if unavoidable and (3) monitor the safety and efficacy of the new product if switching occurs.

Lipid peroxidation of IV lipid emulsions in TPN bags: The influence of tocopherols

Four commercial i.v. lipid emulsions containing soybean oil were investigated to determine the tocopherol content. A sensitive high-performance liquid chromatography (HPLC) on a diol column was established to quantitate the tocopherol isomers in lipid emulsions. A previously described iodometric titration was used to assess the peroxide value (mmol peroxides/L). The pH was measured also. The initial tocopherol concentration ranges in three of the four commercial soybean oil-based 20% lipid emulsions studied were compared ([mg/L]: alpha: 17-23, beta: 4, gamma: 88-129, delta: 40-44). One product showed an increased alpha-tocopherol content (172 mg/L) due to supplementation during manufacture. During storage in an ethylvinyl acetate (EVA) bag at 40 degrees C under light-protection (LP) for 34 d, a lipid emulsion 20% with a natural alpha-tocopherol content showed a peroxide value (PV) of 9.18 (about 450 times the value of controls in glass bottles) with a concomittant reduction of the tocopherol isomers to 61.6% (alpha), 86.5% (gamma), and 88.9% (delta) compared to the initial values. Comparison of two lipid emulsions with different amounts of alpha-tocopherol (Lipidem 20%, B. Braun, Switzerland: 156.29 mg/L vs. Intralipid 20%, Pharmacia Upjohn, Switzerland: 8.75 mg/L) for their antioxidative capacity using the same stress conditions revealed for the emulsion with the high alpha-tocopherol content a significantly higher PV over the whole test period (after 5 wk: 33.63 vs. 6.23; P < 0.001) and an increased alpha-tocopherol decomposition (51.6% vs. 8.7%). The drop in pH was higher, also (1.9 vs. 1.0 pH units). In contrast to ordinary concentrations of about 20 mg/L, alpha-tocopherol in 20% lipid emulsions showing antioxidative properties, a supplementation with about 160 mg/L showed a prooxidative effect when exposed to ambient atmosphere in an EVA bag.

In vitro oxidation of IV lipid emulsions in different all-in-one admixture bags assessed by an iodometric assay and gas-liquid chromatography☆

Polyunsaturated fatty acids (FAs) of intravenous (IV) lipid emulsions can peroxidize to potentially harmful lipid hydroperoxides. In order to assess in vitro peroxidation of IV fat emulsions in all-in-one (AIO) admixture bags, an iodometric titration to determine lipid hydroperoxide content expressed by the peroxide value (PV) and a gas-liquid chromatographic (GLC) assay to determine changes of the FA pattern were established. A long-chain triglyceride (LCT) and medium-chain triglyceride-LCT emulsion were compared for the PV and the pH during storage at room temperature and daylight in AIO bags made of ethylvinylacetate (EVA) and polypropylene:polyamide 7:3 (V90). In contrast to storage in glass bottles, significant peroxidation was detected in both emulsions with 0.5-3.4 mmol peroxides/L after 28 d (150 times the control PV). A pH drop of at least 0.3 (EVA) and 1.2 (V90) units was measured. Initial PVs and peroxidation kinetics of the emulsions were different; V90 material showed better barrier properties against oxygen. PV was increased by higher temperature and light exposure. The FA pattern of an LCT emulsion with a PV > 6 (storage: 40°C in a dark room for 28 d in AIO bags) assayed by GLC remained unchanged. The iodometric peroxide and the GLC assay were reproducible and easy to handle. Only the iodometric method was sensitive enough to detect peroxidation effects (detection limit: 0.02 mmol peroxides/L). IV fat emulsions can be checked for lipid hydroperoxide content with the rapid iodometric assay to guarantee optimal quality of IV lipids used for AIO admixtures. To prevent peroxidation, lipids in AIO bags should be stored light-protected in a refrigerator; an oxygen-tight overwrap is mandatory for extended periods.

Different Pharmaceutical Products Need Similar Terminology

In the last decade, discussions on the development of the regulatory framework of generic versions of complex drugs such as biologicals and non-biological complex drugs have attracted broad attention. The terminology used is far from harmonized and can lead to multiple interpretations of legal texts, reflection papers, and guidance documents regarding market introduction as well as reimbursement. This article describes the meaning of relevant terms in different global regions (Europe, USA, WHO) and offers a proposal for a globally accepted terminology regarding (non-) biological complex drugs.

Nanoparticle iron medicinal products - Requirements for approval of intended copies of non-biological complex drugs (NBCD) and the importance of clinical comparative studies.

Currently, most countries apply the standard generic approach for the approval of intended copies of originator nanoparticle iron medicinal products, requiring only demonstration of bioequivalence to a reference medicinal product by bioavailability studies. However, growing evidence suggests that this regulatory approach is not appropriate. Clinical and non-clinical studies have shown that intended copy preparations of nanoparticle iron medicinal products can differ substantially from the originator product in their efficacy and potentially in their safety profile. An adapted regulatory pathway (separate from the standard generic approach) with defined data requirements is needed for approval of intended copies of iron medicinal products. Here, we discuss the difficulties involved in assessing therapeutic equivalence of nanoparticle iron medicinal products and suggest key concepts of a regulatory approach. Standardized non-clinical comparative studies are necessary but, as demonstrated in the reported clinical data, they may not be sufficient to demonstrate a comparable efficacy and safety profile. Validated, prospective, comparative clinical studies might be needed, in addition to non-clinical studies, in order to enable appropriate assessment of therapeutic equivalence. Furthermore, including brand names in addition to the International Non-proprietary Names (INNs) in safety reports could enable effective safety monitoring of intended copies and originator products.

Lipid peroxidation of intravenous lipid emulsions and all-in-one admixtures in total parenteral nutrition bags: the influence of trace elements.

An iodometric titration was used to assess the influence of a daily portion of trace elements on lipid peroxidation of pure lipid emulsions and lipid-containing all-in-one (AIO) admixtures by measuring the peroxide value (PV; mmol peroxides/L). A pure lipid emulsion (Intralipid 20%; Pharmacia & Upjohn, Dubendorf, Switzerland) was stored in ethylvinylacetate bags under light protection (LP) at 40 degrees C with and without trace elements. In absence of trace elements the PV of Intralipid 20% was significantly lower (day 14: 2.77 vs 18.04; p < .001). After the same time period with the same storage conditions the drop in pH was two times higher in presence of trace elements (1.54 vs 0.77). In an AIO admixture with LP stored at 2 degrees C to 8 degrees C, trace elements increased the PV from 0.04 to 0.19 mmol/L (day 29; p < .01). The drop in pH was 0.01 and 0.02 units, respectively. When stored at 20 degrees C to 30 degrees C and exposed to daylight, the PV of the AIO admixture containing trace elements reached 1.92 compared with 0.52 in their absence (day 19; p < .001) with a pH drop of 0.03 and 0.11, respectively (day 29). Although trace elements led to a much higher drop in pH in pure lipid emulsions, no obvious influence on the pH of AIO admixtures was demonstrated. To minimize lipid peroxidation, AIO admixtures should be stored light-protected and refrigerated without trace elements. The latter should be added immediately before administration or should be given separately.