二甘醇对儿童的毒性-Diethylene Glycol Toxicity In Children

dissertation结构

第1章“总论”：这是通过引入到研究相关的关键概念，dissertation绪论，界定的孩子的药品使用问题，突出了药品质量的概念，定义伪劣药品和勾勒dissertation的结构研究的目的和目标的问题。

第2章“二甘醇对孩子的毒性”：这是根据所有相关的出版物的审查日期以总结DEG中毒包括流行病学，毒性的主要方面，毒性机制，临床表现，诊断和管理。它也表明了在没有药物的质量控制体系情况下可以发生什么。


Structure of thesis

Chapter 1 - “General Introduction”: this acts as a preface to the thesis by introducing the key concepts of relevance to the research, defining the problems of children‟s access to medicines, highlighting the concept of drug quality, defining the problem of drug counterfeiting and outlining the aims and objectives of the study and the structure of the thesis.

Chapter 2 - “Diethylene Glycol Toxicity in Children”: this presents a review of all the relevant publications to date so as to summarise all the main aspects of DEG poisoning including epidemiology, toxicity, mechanisms of toxicity, clinical features, diagnosis and management. It also demonstrates what can happen in the absence of drug quality control.

Chapter 3 - “Problems of Access to Health Care and Medicines for Asylum Seekers and Refugees – Literature Review“: this discusses the published literature concerning barriers to health care for Asylum Seekers and Refugees. It starts with a general overview first of their background, then of the barriers they might encounter in accessing health care including cultural, communication, financial and health problems.
Chapter 4 - “Problems of Access to Health Care and Medicines for Gypsies and Travellers – Literature Review“: this presents the literature review related to the current investigation into the “at risk” groups - Gypsies and Travellers. The chapter discusses the relevant published literature and addresses all the aspects of, and barriers relating to, their access to health care.
Chapter 5 - “Methodology”: this concerns the data-gathering instrument for this study. The last parts of this chapter describe the interview schedule and guide, the ethical considerations and analysis processes.
Chapter 6 - “Results and Discussion”: this presents and discusses the data gathered from the interviews of the Asylum Seeker and Refugee parents who were involved in this study.
Chapter 7 - “Results and Discussion”: this presents and discusses the data gathered from the interviews of the Gypsy and Traveller parents who were involved in this study.
Chapter 8 - “General discussion and Conclusion”: this brings together all the key findings from this work. The discussion considers and highlights the main research findings and their wider implications, while the conclusion summarises them. It also offers recommendations and suggestions for both future research and further improvements1.7 Summary
Children have the right to access to safe and effective medicines. This means that work needs to be done to improve the availability of safe standard paediatric formulations and, simultaneously, to ensure better access to them (75). Therefore, this study considers children‟s access to safe medicines and highlights the problem of substandard and counterfeit medicines.

CHAPTER TWO
DIETHYLENE GLYCOL TOXICITY IN CHILDREN
二甘醇对儿童的毒性

1  Introduction引言
The problem of substandard and counterfeit medicines has been highlighted in the previous chapter. In this chapter, I have focused on the specific problems associated with a highly toxic excipient – diethylene glycol (DEG). This example illustrates the significant toxicity of substandard and counterfeit medicines especially in children.
There have been several epidemics where predominantly young children have presented with an acute onset of renal failure. Incidents of mass poisoning with DEG have occurred in a variety of countries over the last 20 years, with more than 300 children having died as a consequence. These deaths have occurred in separate incidents in different countries from three continents (64, 66, 76-78). The deaths were due either to the contamination (64, 66, 78) of medicinal products by DEG or the deliberate illegal use of DEG as a solvent in a medicinal product (76, 77).

Symptoms of DEG poisoning include renal and liver failure, seizures and gastro-intestinal bleeding. Outbreaks of unexplained renal failure should raise particular concern. Early recognition of DEG poisoning within the community is likely to prevent further deaths, by the removal of the contaminated/illegal medicines.

DEG consists of two ethylene glycol molecules joined by an ether bond. Although first produced in France in 1869, commercial production did not begin until 1928. It proved useful in a variety of industrial settings as an excellent solvent or ingredient in consumer products including antifreeze, brake fluids, lubricants, cosmetic creams, inks, dyeing agents and binding adhesive (75). It has also been used as a softening agent for textiles, paper and packaging materials. It unfortunately has a sweet taste which makes it appealing to children.

The aim of reviewing the literature was to summarise all the main aspects of DEG poisoning including epidemiology, toxicity, mechanisms of toxicity, clinical features, diagnosis and management.

2   Methods方法
A review of DEG poisoning was undertaken. A literature search in the MEDLINE, EMBASE, and Pub Med databases (1960-2009) was performed (Figure 1). Key words were diethylene glycol, toxicity, symptoms and management. The search was restricted to data from humans and papers published in English. All articles that mentioned diethylene glycol were reviewed. The following data from the publications were extracted; number of children and adults affected, clinical signs and symptoms, management and the cause of the outbreak. Duplicates and unrelated abstracts were excludedFigure 2.1: Flow Chart

2.4 Results结论
Eighty one abstracts were identified. The 13 duplications were removed leaving a total of 68 publications. Four of these were in languages other than English. The 64 remaining articles were read and eight of them were considered to be not relevant. This left a total of 56 publications from which the data was extracted.

3 Clinical signs and symptoms临床症状体征
Most victims of DEG poisoning have a variety of clinical signs and symptoms depending on the amount and duration of the exposure. During the first period of ingestion, intoxicants stimulate gastrointestinal discomfort which usually begins with nausea, vomiting, diarrhoea, abdominal pain and bleeding. Other later symptoms include oliguria, anuria, metabolic acidosis, liver failure, seizures and acute renal failure (Table 2.1).

Table 2.1: Signs and symptoms of DEG poisoning Gastrointestinal Nausea, vomiting, diarrhoea, abdominal pain and bleeding, anorexia Urinary Diuresis, oliguria, anuria, acute renal failure, flank pain, proteinuria Neurological CNS depression, encephalopathy, seizures, tremors, weakness, lethargy, malaise, coma Hepatic Hepatitis, hepatomegaly Cardiovascular Hypertension, hypotension, cardiac dysrhythmias Respiratory Dyspnoea, tachypnoea, pulmonary oedema Metabolic Metabolic acidosis Haematological Anaemia Others Fever

4  What effect does DEG have on the body?对身体的影响程度？
Information obtained over the past few decades has demonstrated that DEG is a powerful nephrotoxic and neurotoxic poison (75, 79). There are some uncertainties regarding the principle cause of renal toxicity and neurological effects in DEG poisoning. Some have raised concern that renal toxicity may be induced by the parent compound, but others feel that toxic effects are related to the metabolites. DEG is converted to 2-hydroxyethoxyacetic acid (HEAA) via oxidation by alcohol dehydrogenase.
The minimum lethal dose of DEG in humans is uncertain. There appears to be a wide range in relation to toxicity. Analysis of the data from an outbreak in Haiti suggested that the minimum lethal dose was 0.35 mg/kg (64). However, an outbreak that occurred in Argentina involving adults (age range 50-93 years) suggested that the minimal lethal dose for adults is likely to be between 0.014 and 0.170 mg/kg (79).

5  Previous episodes of DEG poisoning DEG中毒的早期经验教训
The first reported episode of poisoning in association with the use of DEG in a medicine was in 1938 (80). DEG was used as a solvent in the preparation of sulphanilamide elixir. The makers of the product were unaware of the toxicity of DEG. It is estimated that there were 105 deaths of which one third were those of children (80). Following this episode, legislation was introduced in the US that required formulations of new medicines to be tested for safety. Since then there have been numerous other reported cases of DEG poisoning. Following the episode in the USA in the 1930s, there have been five other instances where DEG has been used as a solvent.

There have been eight episodes where a medicinal product has been contaminated with DEG (64, 66, 78, 79, 84-88) (Table 2.3).
Table 1: Contamination with DEG
The number of deaths per outbreak has ranged from one to over 200. The time taken to recognise that the outbreak was associated with DEG poisoning has been a major contributing factor to the number of deaths; i.e., the sooner it is recognised that this is DEG poisoning, the fewer the deaths. Unfortunately, even with prompt recognition, as in Nigeria 2008, following the use of a teething formula that was contaminated with DEG, there can still be a large number of deaths (66, 88). This particular incident was probably associated with a high number of fatalities (84 Year Country Deaths in children Overall deaths Overall cases Duration (months) Drug Reference 1986 India 14 14 14 0.5 Glycerine (84) 1992 Argentina 0 15 29 – Upper Respiratory Tract infections (URIs) medicinal agent (Propolis syrup) (79)
children died) because of the young age of the patients exposed to the contaminated product. There have also been cases of contamination of toothpaste affecting adults in both the USA and Spain (89, 90). Fortunately there were no deaths. Why does DEG poisoning occur?

All medicines contain a variety of excipients and solvents alongside the active drug. This is to make the medicine palatable or soluble. No major pharmaceutical company would deliberately use DEG as a solvent because they are all aware of its toxicity. Unfortunately the financial profit from medicines is huge and because of this there is a proliferation of smaller manufacturers who will make unacceptable economies to maximise profits (91, 92).
In many cases, the individual/company responsible for the use of DEG as a solvent is not identified. However, judicial investigations in China identified the pharmaceutical company that deliberately used DEG as a solvent (83). Five individuals from the company were subsequently jailed for between four and seven years and the Deputy Director of the Food and Drug Administration of the region was sacked for negligence 2.4.5 Can we prevent future episodes?
The WHO has recognised the importance of ensuring that medicines are prepared safely. They have established WHO Good Manufacturing Practice Guidelines (1969) and also established a certification scheme (1975) to ensure the quality of pharmaceutical preparations sold in international markets (66, 94). These efforts will help to improve the quality of medicines available especially within low and lower-middle income countries. It is essential that Departments of Health and national regulatory agencies support these efforts.
 

 6 When to suspect DEG poisoning 什么时候开始怀疑是DEG中毒

Despite the numerous deaths that have occurred in children due to DEG poisoning, the vast majority of health professionals worldwide will fortunately never see a case. The key issue, however, is for health professionals who see more than one case of acute unexplained renal failure in children to be aware that DEG poisoning is a possibility. It is established that adverse drug reactions are often not recognised (95). The lack of awareness of possible drug toxicity is even greater in relation to the toxicity of excipients (96). Additionally, the signs and symptoms in association with DEG poisoning (Table 2.2) are extremely diverse. Rare causes of acute renal failure such as primary hyperoxaluria may affect a single individual but will not result in an outbreak. Doctors and pharmacists involved in renal units alongside those involved in public health, however, should be aware of the possibility of DEG poisoning, especially if they work in low- and middle-income countries.

Management 管理
A case report of young children ingesting poisons such as brake fluid which contains DEG has highlighted the possibilities of enhancing the clearance of DEG (97). This case report alongside others (98) has suggested the use of fomepizole which is an alcohol dehydrogenase inhibitor that can be administered intravenously (97, 98). Fomepizole (4-methylpyrazole) is increasingly being used in adults and children following poisoning with methanol or ethylene glycol (99). It has minimal toxicity and a dose of 15 mg/kg is recommended over a 30-minute time period. A further 10 mg/kg can be administered at 12 hour intervals (99, 100).
In the case report involving a child (97), haemodialysis was used and this was associated with a fall in the plasma concentration of DEG. If concurrent haemodialysis is used then the fomepizole can be administered over four hours (99). These case reports were associated with a good clinical outcome, but hospitals in communities where poisoning usually occurs are extremely unlikely to be able to cope with an outbreak involving large numbers of children experiencing acute renal failure. DEG poisoning unfortunately usually occurs in those communities with the poorest access to health care. If available, fomepizole and haemodialysis are the treatment of choice for children with acute renal failure (101). Options which are more likely to be available in low-income countries include peritoneal dialysis and oral ethanol (0.8-1.0 ml/kg loading dose followed by 0.15 ml/kg/h of 95% ethanol diluted in orange juice)(101). Ethanol, although cheaper, is more toxic than fomepizole and is often not available (102, 103'

Summary 摘要
With the increase in proliferation of counterfeit medicines, DEG poisoning is unfortunately likely to occur again. The sudden outbreak of an epidemic of acute renal failure among children should make individuals consider the possibility of DEG poisoning as a cause. Without any action against this kind of medicines counterfeiting, the problem will increase and the result will be further deaths of children due to poisoning outbreaks (51).
The episodes of DEG poisoning illustrate the problems associated with counterfeit medicines. They also illustrate what can happen if there are no strict regulations on drug manufacturing (54). It is highly likely that not all outbreaks of DEG poisoning have been identified.

This chapter has focused on reviewing the literature in relation to DEG poisoning. The following chapter reviews the literature in relation to the problems experienced by Asylum Seekers and Refugees.

CHAPTER THREE
PROBLEMS OF ACCESS TO HEALTH CARE AND MEDICINES FOR ASYLUM SEEKERS AND REFUGEES
寻求庇护者和难民的医疗保障及药物使用问题

Review of Literature
1  Introduction
This chapter will explore the literature related to the access to health care and medicines in some groups of ethnic minorities such as Asylum Seekers, Refugees, Aboriginals, and Latino American.
This will encompass a number of areas in order to provide a comprehensive background to the exploration of the concept of access to health care, identification and categorisation of specific barriers to medicines and healthcare. It will also examine access among the children of these minority groups.

2  Method
Literature searches of computer databases were performed using OVID, MEDLINE (data range, 1950-April 2012), EMBASE (data range, 1980-April 2012), CINAHL and Pub Med (updated to April 2012), Google Scholar (updated to April 2012), published in English, with text and medical subject headings. In addition, manual searches of the reference list of relevant studies were used to identify further appropriate papers.
Main inclusion criteria
The following key criteria were used to refine the search and to identify material that would be included in this literature review:
• Sources covering the last 30 years
• Evidence-based research
• Publications in English, including peer review articles, extracts from books, case studies, anecdotal reports, government and other reports, and primary researches
• Articles relating to the following terms, health care access, utilisation, ethnic minorities, Asylum Seekers, Refugees, children‟s access, and access barriers to health care and/or medicines.

Main exclusion criteria
• Unrelated abstracts
• Duplicate articles
• Non- English sources
• Other publications not compatible with the inclusion criteria.

3 Results
680 abstracts of publications were identified. Duplicates and unrelated abstracts were excluded. The resulting publications were then limited to papers published in English of which full texts were obtained and screened further to exclude studies not compatible with the inclusion criteria. Ultimately, 104 published papers relating to children‟s access to health care were included in this literature review (Figure 3.1). Many of the articles I have referred to are review articles. However to further explain specific points in these review articles I have referred back to the original papers mentioned in these reviews. This is the reason why my literature review contains references to many old papers. The format of these papers is presented in table (3.1The results will be presented and discussed in four broad themes which have emerged from reviewing the literature:
• The first section explores the concept of access to health care and medicines, involves definition of access to health care and discusses equality of access.
• The second section presents an overview of the concept of “at risk” groups, defining the terms „Asylum Seeker‟ and „Refugee‟ and providing background information for both groups.
• Section three presents an overview of the „at risk‟ children‟s access which also considers the barriers to health care they experienced.

• Section four focuses on both general and specific barriers to accessing health care and medicines which arise from problems not only in the country of origin but also in the host country.
These include legal rights, medical screening, detention, housing, economic factors, GP-related barriers, health records, language barriers, mental health barriers, cultural barriers, stigma and isolation (table 3.2).