Multiple emulsions: an overview

Multiple emulsions are complex polydispersed systems where both oil in water and water in oil emulsion exists simultaneously which are stabilized by lipophillic and hydrophilic surfactants respectively. The ratio of these surfactants is important in achieving stable multiple emulsions. Among water-in-oil-in-water (w/o/w) and oil-in-water-in-oil (o/w/o) type multiple emulsions, the former has wider areas of application and hence are studied in great detail. Formulation, preparation techniques and in vitro characterization methods for multiple emulsions are reviewed. Various factors affecting the stability of multiple emulsions and the stabilization approaches with specific reference to w/o/w type multiple emulsions are discussed in detail. Favorable drug release mechanisms and/or rate along with in vivo fate of multiple emulsions make them a versatile carrier. It finds wide range of applications in controlled or sustained drug delivery, targeted delivery, taste masking, bioavailability enhancement, enzyme immobilization, etc. Multiple emulsions have also been employed as intermediate step in the microencapsulation process and are the systems of increasing interest for the oral delivery of hydrophilic drugs, which are unstable in gastrointestinal tract like proteins and peptides. With the advancement in techniques for preparation, stabilization and rheological characterization of multiple emulsions, it will be able to provide a novel carrier system for drugs, cosmetics and pharmaceutical agents. In this review, emphasis is laid down on formulation, stabilization techniques and potential applications of multiple emulsion system.     

Brief overview of chemical terrorism and its consequences

The article deals with chemical terrorism as a current security risk and its possible impacts on population and infrastructure. It also discusses aspects and implementation of biological, radiological, and nuclear terrorism. The 1995 attack by sarin in the Tokyo underground is briefly mentioned. The effects of chemical warfare agents and chemical toxic substances and the possibilities of their abuse by terrorists are thoroughly discussed. Based on computer modeling of impacts of attacks by chemical toxic substances, the authors present opinions on their possible abuse for acts of terrorism. They also discuss methods of protecting against chemical attacks used in the Czech Republic such as protective masks or new therapy after nerve gas attacks. Novel technical means of decontamination after an act of chemical terrorism are also considered.     

Detection of low-level environmental chemical allergy by a long-term sensitization method

Multiple chemical sensitivity (MCS) is characterized by various signs, including neurological disorders and allergy. Exposure may occur through a major event, such as a chemical spill, or from long-term contact with chemicals at low levels. We are interested in the allergenicity of MCS and the detection of low-level chemical-related hypersensitivity. We used long-term sensitization followed by low-dose challenge to evaluate sensitization by well-known Th2 type sensitizers (trimellitic anhydride (TMA) and toluene diisocyanate (TDI)) and a Th1 type sensitizer (2,4-dinitrochlorobenzene (DNCB)). After topically sensitizing BALB/c mice (9 times in 3 weeks) and challenging them with TMA, TDI or DNCB, we assayed their auricular lymph nodes (LNs) for number of lymphocytes, surface antigen expression of B cells, and local cytokine production, and measured antigen-specific serum IgE levels. TMA and TDI induced marked increases in levels of antigen-specific serum IgE and of Th2 cytokines (IL-4, IL-5, IL-10, and IL-13) produced by ex vivo restimulated lymph node cells. DNCB induced a marked increase in Th1 cytokine (IL-2, IFN-γ, and TNF-α) levels, but antigen-specific serum IgE levels were not elevated. All chemicals induced significant increases in number of lymphocytes and surface antigen expression of B cells. Our mouse model enabled the identification and characterization of chemical-related allergic reactions at low levels. This long-term sensitization method would be useful for detecting environmental chemical-related hypersensitivity.     

Inflammatory responses in RAW264.7 macrophages caused by mycobacteria isolated from moldy houses

Mycobacterial strains (nonpathogenic Mycobacterium terrae, potentially pathogenic Mycobacterium avium-complex and Mycobacterium scrofulaceum), isolated from a moldy building, were studied with respect to their ability to stimulate macrophages (RAW264.7) to produce inflammatory mediators, and to cause cytotoxicity. Reactive oxygen species (ROS) were measured by chemiluminescence, cytokines (TNF-, IL-6, IL-1, IL-10) immunochemically, nitric oxide (NO) by Griess-method, expression of inducible NO-synthase (iNOS) with Western Blot analysis and cytotoxicity with MTT-test. All the strains induced dose- and time-dependent production of NO, IL-6 and TNF- in macrophages, whereas IL-1 or IL-10 production was not detected. The production of ROS and cytotoxicity was increased with the highest doses. Interestingly, different strains had significant differences in their ability to induce these responses, M. terrae being the most potent and M. avium-complex the weakest one. These results indicate that both non- and potentially pathogenic strains of mycobacteria present in moldy buildings are capable of activating inflammatory mechanisms in macrophages.     

Setting an indoor air exposure limit for formaldehyde: factors of concern

The paper aims to evaluate the indoor air limit of 1 μg/m³ (0.8 ppb) formaldehyde as advised by the European Commission [the INDEX project; Kotzias, D., Koistinen, K., Kephalopoulos, S., Schlitt, C., Carrer, P., Maroni, M., Jantunen, M., Cochet, C., Kirchner, S., Lindvall, T., McLaughlin, J., Mølhave, L., de Oliveira Fernandes, E., Seifert, B., 2005. Critical appraisal of the setting and implementation of indoor exposure limits in the EU. European Commission, Institute for Health and Consumer Protection, Physical and Chemical Exposure Unit, Ispra, Italy, pp. 1–50]. The limit has been based on a nose and throat irritation threshold of 0.1 mg/m³ (0.08 ppm; LOAEL), a NOAEL of 0.03 mg/m³ (0.025 ppm) and an assessment factor of 30, including a factor of 3 for the higher sensitivity of children.     

Indoor exposure to chemical and biological agents and health efects in primary school children

The aim of this study has been to estimate effects of indoor air pollutants on children’s health. An anamnestic retrospective study was done on 1074 children aged between 7 and 11 years old who lived in Nis (Serbia). An original questionnaire was used in an interview between training physicians and children’s parents. Interview data were processed by using Microsoft Excel and Epiinfo 6. The investigation determined that children who were more often exposed to combustion by-products had respiratory and nonspecific symptoms. Parental smoking was strongly associated with wheezing, bronchitis, headache and fatigue. There was no association between health and keeping pets, apart from partial nasal congestion. Presence of insects (e.g., cockroaches) and rats in households was a significant risk factor for all symptoms and diseases estimated except for asthma and pneumonia. Homes abundant in textiles were the cause of nasal congestion, wheezing and fatigue in children. Old mattresses were associated with respiratory symptoms, bronchitis, and nonspecific symptoms. It has been concluded that indoor air quality plays a major role in children’s health. Sources of indoor air pollution are present in every home. Being aware of the risks associated with indoor air quality problems, consequently, leads to their mitigation.     

野木瓜化学成分及其药理和临床研究进展

目的综述有关中药野木瓜的化学成分、药理作用及临床应用方面的研究进展。方法对近年来国内外期刊中有关文献进行检索和综述。结果野木瓜含有多种化学成分,主要有去甲五环三萜皂苷类化合物、木脂素苷类化合物、黄酮类和酚性成分等;药理作用方面,野木瓜具有镇痛抗炎、阻滞神经传导、放射增敏、抑制胃肠道平滑肌等药理活性;临床应用方面,野木瓜主要用于治疗腰椎间盘突出症、腰椎骨质增生、三叉神经痛、坐骨神经痛、神经性头痛、风湿关节痛等疾病。结论中药野木瓜资源丰富,具有多种生物活性,特别是镇痛抗炎活性显著,开发应用前景广阔。     

Essential (“Precursor”) chemical control for heroin: Impact of acetic anhydride regulation on US heroin availability

Background

To reduce heroin availability, the United Nations (UN) has encouraged nations to control acetic anhydride, an essential (“precursor”) chemical typically necessary to the drug's production. This effort, a major environmental prevention policy, has received little evaluation. The United States, per the UN's lead, implemented acetic anhydride regulation in 11/1989. The present study examines whether the US regulation impacted US heroin availability.

Methods

Monthly series of three heroin availability indicators—heroin purity, heroin price, and amount of heroin seized—were constructed for the conterminous United States, the US Southwest (supplied predominantly with Mexican-produced heroin), and the US Northeast (supplied predominantly, at the time, with Southeast Asian-produced heroin). Data came from the System to Retrieve Information from Drug Evidence (01/1987–04/2011). Impacts were assessed using ARIMA-intervention time series analysis.

Results

In each US area, heroin purity and amount seized rose and price decreased throughout the pre-intervention period. All of the indicators then reversed course at the time of the regulation. In the conterminous United States, the US Northeast, and the US Southwest, purity decreased (−40%, −25% and −50%, respectively); amount seized decreased (−27%, −37% and −39%, respectively); and price rose (+93%, +102% and +296%, respectively). Impacts lasted 2–5 years.

Conclusion

US heroin availability decreased in association with the US acetic anhydride regulation. The impacts in the US Southwest and US Northeast suggest that heroin production in Mexico and Southeast Asia, respectively, was constrained. This study lends support to the contention that essential (“precursor”) chemical control can be used to help address heroin.     

Toxicity of airborne dust as an indicator of moisture problems in school buildings

Moisture-damaged indoor environments are thought to increase the toxicity of indoor air particulate matter (PM), indicating that a toxicological assay could be used as a method for recognizing buildings with indoor air problems. We aimed to test if our approach of analyzing the toxicity of actively collected indoor air PM in vitro differentiates moisture-damaged from non-damaged school buildings. We collected active air samples with NIOSH Bioaerosol Cyclone Samplers from moisture-damaged (index) and non-damaged (reference) school buildings (4?+?4). The teachers and pupils of the schools were administered a symptom questionnaire. Five samples of two size fractions [Stage 1 (>1.9?μm) and Stage 2 (1–1.9?μm)] were collected from each school. Mouse RAW264.7 macrophages were exposed to the collected PM for 24?h and subsequently analyzed for changes in cell metabolic activity, production of nitric oxide (NO), tumor necrosis factor (TNF)-α and interleukin (IL)-6. The teachers working in the moisture-damaged schools reported respiratory symptoms such as cough (p?=?0.01) and shortness of breath (p?=?0.01) more often than teachers from reference schools. Toxicity of the PM sample as such did not differentiate index from reference building,s but the toxicity adjusted for the amount of the particles tended to be higher in moisture-damaged schools. Further development of the method will require identification of other confounding factors in addition to the necessity to adjust for differences in particle counts between samples.     

Ventilator-associated pneumonia: an overview

Despite aggressive efforts to reduce nosocomial infections, many intubated patients develop ventilator-associated pneumonia (VAP). VAP has been an area of intense research; however, there is still little consensus in the literature on how to accurately diagnose or treat VAP. VAP complicates the course of 8 – 28% of mechanically ventilated patients and mortality varies greatly from 8 to 76%, depending on the specific population being studied. Once pneumonia is suspected, bacteriologic confirmation should be obtained and empiric therapy must be instituted as soon as possible, as a delay in therapy or inappropriate therapy greatly increases mortality. Initial antibiotic therapy should be based on the most common organisms in each hospital or unit, and the most likely pathogens for that specific patient. Constant surveillance of the responsible pathogens through the use of antibiograms allows clinicians to make educated choices for antibiotics. When final cultures and sensitivities are available, de-escalation to less broad spectrum antibiotics should be performed. If cultures show no bacterial growth, antibiotics should be discontinued so that patients are not exposed to unnecessary antibiotics. Following these practices will help to decrease multi-resistant strains of bacteria and can improve the morbidity and mortality of VAP.     

Carrier erythrocytes: an overview

Application of erythrocytes, the most abundant cells of the human body with desirable physiologic and morphologic characteristics, in drug delivery has been exploited extensively. These cellular carriers, having remarkable biocompatibility, biodegradability, and life-span in circulation, can be loaded by a wide spectrum of compounds of therapeutic value using different chemically, as well as physically, based methods. Most of the characteristics of the erythrocytes, including shape, membrane fragility, deformability, and hematologic indices undergo some degree of irreversible changes during the loading procedure. The efflux pattern of the encapsulated compounds from the carrier erythrocytes covers a wide range between a relatively rapid release (complete release within a few hours) and no detectable release until the cell lysis. A series of methods have been tested successfully for improvement of in vitro storability of the carrier erythrocytes without any significant changes in cell biology as well as drug delivery efficacy. Carrier erythrocytes have been exploited for several potential applications, including intravenous slow release of therapeutic agents, enzyme therapy, drug targeting to reticuloendothelial system (RES), improvement of oxygen delivery to tissues, and preparation of fused cells.     

Multiple Sclerosis: Pathogenesis and Treatment

Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease of the central nervous system. It affects approximately 400,000 people in the United States and onset is usually during young adulthood. There are four clinical forms of MS, of which relapsing remitting type is the most common. As the etiology of MS is unknown, finding a cure will remain challenging. The main mechanism of injury appears to be inflammation and 8 agents are now FDA approved to help control MS. These agents for relapsing forms of MS target different parts of the immune system, with the end goal of decreasing and avoiding further inflammation. No agents are FDA approved for the primary progressive version of MS. FDA approved agents include four preparations of interferon β (Avonex, Rebif, Betaseron and Extavia), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), natalizumab (Tysabri) and fingolimod (Gilenya). There are several drug undergoing phase II and III trials. The heterogeneity of the MS disease process, individual patient response, and medication toxicities continue to challenge the treating physician.     

Night eating syndrome: an overview

Objectives The purpose of this review is to outline the nosographic characteristics of NES and the most reliable ethiopathogenetic theories in relation to the most recent evidence in the literature. Key findings The night eating syndrome (NES) is a disorder occurring at the stated time, that does not meet the criteria for any specific eating disorder. NES is characterized by a reduced feeding during the day, evening hyperphagia accompanied by frequent nocturnal awakenings associated with conscious episodes of compulsive ingestion of food and abnormal circadian rhythms of food and other neuroendocrine factors. Frequently it is associated with obesity and depressed mood. We highlight the therapeutic possibilities of some drugs, especially selective serotonin re‐uptake inhibitors (SSRIs), which reduce the hyperactivity of the serotonin transporter in NES and significantly improve the clinical picture of this disease. Conclusions Night eating syndrome is of importance clinically because of its association with obesity. The recognition and effective treatment of NES may be an increasingly important way to treat a subset of the obese population. Treatment of the syndrome, however, is still in its infancy. One clinical trial has reported efficacy with the SSRI sertraline. Other treatments, such as the anticonvulsant topiramate, phototherapy, and other SSRIs, may also offer future promise. Particularly useful would be studies involving brain scans (magnetic resonance imaging or single‐photon emission computed tomography) of patients with NES compared with the healthy population, to investigate more thoroughly the possible alterations involved in the pathogenesis of NES.     

Susceptibility and risk: an overview

This symposium on susceptibility and risk was the third in a series designed to bring together experts from diverse disciplines to discuss contemporary issues in risk assessment. The topic in 1996 was especially challenging since susceptibility is influenced by a myriad of factors including environmental, genetic, social and political elements. The delineation of the relative contribution of various ‘susceptibility' factors has major implications for risk management options that may be applied in a regulatory context (risk prevention and risk reduction) or by the individual (risk avoidance). Current approaches to account for susceptibility in risk assessments (e.g. application of an uncertainty factor) have frequently been challenged as to their scientific basis and thus need periodic re-examination or update to maintain a credible foundation for the assessment process. The goal of this symposium was to gain a better understanding of the dimensions of the problem and to explore the directions that the risk assessment process might follow to better quantify the contribution of susceptibility in risk calculations.     

Ketorolac tromethamine formulations: an overview

Ketorolac tromethamine (KT) is a non-steroidal anti-inflammatory drug that belongs to the class of heteroaryl acetic acid derivatives. It is a non-selective cyclooxygenase (COX) inhibitor, being marketed in the racemate form. Most of its analgesic and COX inhibitory activity is retained in the S-isomer. Ketorolac is administered as its tromethamine salt orally, intramuscularly, intravenously and as a topical ophthalmic solution. The frequent occurrence of gastrointestinal disturbances including gastrointestinal bleeding, perforation and peptic ulceration along with the short mean plasma half-life (t_1/2 ～ 5.5 h) has prompted for the development of various formulation strategies for the appropriate delivery of KT. The article gives an overview of the main concepts used thus far to design various pharmaceutical dosage forms for the therapeutically effective delivery of the drug candidate through various routes. At present, a great deal of emphasis is being placed on the development of sustained release forms for the drug as this would aid in achieving the required therapeutic efficacy and better tolerance with fewer gastrointestinal side effects.     

Genetics of alcoholism: an overview

There is little doubt that human alcoholism carries a significant genetic risk factor. Studies in Scandinavia over many years and more recently elsewhere have clearly shown this relationship. However, we do not know what characteristics or determinants of alcoholism are inherited and this is the focus of current research. Animal genetic studies have contributed to the field and promise to be even more important in the future in defining the neurochemical basis of behavior observed in human alcoholics. The premise that understanding the enzymology and genetics of alcohol metabolism alone would solve the alcoholism problem has not materialized in spite of major advances in the understanding of the enzymes responsible for ethanol metabolism.     

Methods for time‐varying exposure related problems in pharmacoepidemiology: An overview

Purpose

Lack of control for time‐varying exposures can lead to substantial bias in estimates of treatment effects. The aim of this study is to provide an overview and guidance on some of the available methodologies used to address problems related to time‐varying exposure and confounding in pharmacoepidemiology and other observational studies. The methods are explored from a conceptual rather than an analytical perspective.

Methods

The methods described in this study have been identified exploring the literature concerning to the time‐varying exposure concept and basing the search on four fundamental pharmacoepidemiological problems, construction of treatment episodes, time‐varying confounders, cumulative exposure and latency, and treatment switching.

Results

A correct treatment episodes construction is fundamental to avoid bias in treatment effect estimates. Several methods exist to address time‐varying covariates, but the complexity of the most advanced approaches—eg, marginal structural models or structural nested failure time models—and the lack of user‐friendly statistical packages have prevented broader adoption of these methods. Consequently, simpler methods are most commonly used, including, for example, methods without any adjustment strategy and models with time‐varying covariates. The magnitude of exposure needs to be considered and properly modelled.

Conclusions

Further research on the application and implementation of the most complex methods is needed. Because different methods can lead to substantial differences in the treatment effect estimates, the application of several methods and comparison of the results is recommended. Treatment episodes estimation and exposure quantification are key parts in the estimation of treatment effects or associations of interest.