Cytoxan
Christina M. Davidson, MD
- Assistant Professor
- Division of Maternal Fetal Medicine
- Department of Obstetrics and Gynecology
- Baylor College of Medicine
- Houston, Texas
These epigenome-environment interactions can provide an adaptive advantage but in other cases can disrupt the epigenome to alter physiology and increase disease susceptibility in adulthood treatment venous stasis order genuine cytoxan on-line. Remarkably treatment quinsy generic cytoxan 50mg free shipping, although persistent into adulthood treatment modalities order cytoxan overnight, the impact of this reprogramming was metabolically silent until a later-life challenge with a Western-style diet high in fat treatment rheumatoid arthritis discount cytoxan 50mg fast delivery, fructose, and cholesterol. These data reveal that an early-life environmental exposure can impact metabolic health across the life course by inducing loss of epigenomic plasticity and accelerating epigenetic aging, resulting in persistent epigenetic reprogramming that can drive metabolic dysfunction in adulthood. The session will span a continuum of complementary methodological approaches, from flow-mediated dilation in humans to angiogenesis assays in vitro and in vivo. Primary Endorser: Stem Cells Specialty Section Other Endorser(s): Mechanisms Specialty Section; Metals Specialty Section Humans are exposed to metals on a daily occurrence. These exposures can occur during all stages of life, and could result in toxic effects in all organ systems, leading to aberrations in development and other biological processes. Mechanisms underlying these differences and in breast cancer formation induced by this heavy metal will be presented. Barchowsky #1678 8:41 Muscle Stem Cells and Myogenic Targets of Methylmercury Toxicity. Primary Endorser: Clinical and Translational Toxicology Specialty Section Other Endorser(s): Mechanisms Specialty Section; Regulatory and Safety Evaluation Specialty Section Systems toxicology is a transformational subdiscipline within toxicology that applies approaches from systems biology to toxicology related questions. The session will bring together several advances within systems toxicology that are focused on diverse applications and opportunities in drug safety. Each presenter will share examples of successes and challenges they have experienced with applying omic methods, definitive approaches. The first talk will provde an overview of the challenges inherent in extrapolating safety signals across species to understand human risk. Immune responses provide a natural model to facilitate our understanding of complex and interactive events, and the second talk will address immunotoxicity in the context of systems approaches that can be applied to understanding the complexity of immune system interactions. The third presentation will focus on the promise and challenges of microphysiological platforms in systems toxicology. The final talk will provide mechanistic insights into species-specific metabolism, with emphasis on how systems approaches can facilitate the selection of biomarkers consistent with rat and human biology. Key insights about how computational models can serve as platforms for contextualizing experimental data and making functional predictions will be shared. The collective content of the session will highlight how we might use sophisticated, integrated systems and modeling to inform safety decisions in drug discovery. Abstract # #1682 8:00 Systems Toxicology Approaches to the Science of Safety Evaluation. Davis #1686 10:04 Reconciling Rat and Human Liver Genome Scale Metabolic Networks. Primary Endorser: Molecular and Systems Biology Specialty Section Other Endorser(s): Neurotoxicology Specialty Section; Reproductive and Developmental Toxicology Specialty Section Brain health is essential for human well-being across all life stages. Brain development and function are impacted by both genetic and environmental factors. Environmental factors, including exposure to environmental contaminants, are implicated in the etiology of a number of developmental, psychiatric, and neurode generative disorders. The zebrafish is a powerful model for assessing the impact of toxicants on brain development and function. Zebrafish embryos are externally fertilized, which enables direct exposure of the developing embryo, obviating the requirement for maternal exposures. In addition, developing embryos are trans parent, which allows for in vivo imaging of the developing brain. Overall, development occurs rapidly, including formation of the nascent nervous system by three days of life. In this session, researchers will describe how they have leveraged the zebrafish model to investigate different mechanisms of action by which toxicant exposure alters brain development and function. The second talk will introduce the microbiota-gut-brain axis and how developmental exposure to exogenous estradiol compromises neurobehavioral development in a microbiota-dependent manner. The fourth presentation will show a mechanistic link between domoic acid exposure, myelination defects, and impaired startle response. An excellent 2018 zebrafish session surveyed the multiple uses for larval and adult zebrafish including screening environmental chemicals for developmental toxicity, identifying epilepsy drugs, examining chemical uptake, and the assessing of the effects of early-life chemical exposures on adult behavior or transgenerational epigenetic changes. This 2019 session, however, will focus solely on the developing nervous system and all presentations will be mechanistically focused. In addition, perturbation of these systems by toxicant exposures will reveal linkages between these core neurodevelopmental processes and phenotypic outcomes like hyperactivity, seizures, abnormal startle responses, and blood-brain barrier maintenance and function. Abstract # #1687 8:00 Using Zebrafish as a Model to Understand and Ultimately Prevent Neurotoxicity. Systems approaches are quickly expanding our ability to assess the impact of endo-xenobiotic exposures on gene expression and metabolism. The workshop will highlight research aimed at deconvoluting the overlapping contributions that endogenous substrate, xenobiotic, and microbi ome-mediated metabolism play in crafting cellular responses to the environment, in pursuit of an improved pharmacogenomic framework for advancing both predictive toxicology and precision-based approaches to medicine. Abstract # #1693 8:00 Emergent Mechanisms of Cytochrome P450 Gene Regulation: Defining an Improved Roadmap toward 21st-Century Pharmacogenomics. Annalora #1698 10:05 Developing the Human Kidney-on-a-Chip: An Enhanced Model System for Assessing Personalized Drug and Xenobiotic Toxicity. However, while high(er) throughput, thesein vitroapproaches are still too slow to address all novel compounds and chemicals occurring in commerce and the environment. Several computational methods have been published for predicting plasma binding for pharmaceuticals and environmental spaces, but the prediction of metabolic rate has been more difficult. These methods draw inferences from chemical structure and physicochemical properties. If the uncertainty and domain of applicability can be characterized and quantified, then these methods would allow for a timely, risk-based prioritization strategy characterizing dose relationships between in vitro bioactivities and predicted human exposure. Presenters will consider the state-of-the-science between traditional and higher-throughput methods, and the associations between them, such as extrapolation techniques, model confidence, acceptable uncertainty, and context applicability. Understanding the state-of the-science in in silico toxicokinetics for government and industry applications will aid the inclusion of such techniques when limited data are available. Abstract # #1699 8:00 Predicting Metabolic Clearance Rates for Drug Leads and Environmental Chemical Risk Assessment. Primary Endorser: Regulatory and Safety Evaluation Specialty Section Other Endorser(s): In Vitro and Alternative Methods Specialty Section; Molecular and Systems Biology Specialty Section Transformative approaches, such as organotypic in vitro models and high content screening, are redefining the science of toxicology. However, the path to their integration in toxicity testing programs remains somewhat elusive. Toxicity testing, a necessary element of product development and the foundation of human health risk assessment, has traditionally relied heavily onin vivo apical endpoints. The advent ofin vitroand computational technologies holds promise to drastically change and improve the testing paradigms of the future. Beyond the obvious benefit of reducing animal testing, embracing high-throughput predictive models can both provide valuable information to aid in molecule design and provide guidance for targeted toxicological testing strategies. This session will focus on innovative methods, such as toxicogenomics, 3D microtissues, and in vitro high content analysis, that are being used to characterize the safety profile of molecules and products, and their application to predictive and mechanistic toxicology testing approaches. Emphasis will be given to methods that are currently being employed to characterize the safety profile of molecules and products and inform decision-making. To this end, experts from industry, government, academia, and non-for-profit were gathered to discuss the current state of-the-science. The talks will present how cutting-edge research tools and next-generation alternative models are being integrated in the safety evaluation of environmental chemicals, pharmaceuticals, and plant protection products. Topics covered will include the value of in vitro transcriptomics to predict in vivo apical findings and identify points of departure; the use of a systems approach to predict and mechanistically classify kidney toxicity in vitro; the use of in silico and in vitro models in discovery toxicology; and the utility of 3D tissue models for screening endocrine disruptors.
The statistical analysis of truncated data: application to theThe statistical analysis of truncated data: application to the Sverdlovsk anthrax outbreak symptoms 0f parkinson disease cytoxan 50 mg on line. Pathology of inhalational anthrax in 42 cases from the Sverdlovsk outbreak of 1979 treatment renal cell carcinoma cytoxan 50mg on line. Epidemic West Nile encephalitis medicine venlafaxine order generic cytoxan online, New York medications safe in pregnancy cheap 50 mg cytoxan with visa, 1999: results of a house hold-based seroepidemiological survey. OriginOrigin of the West Nile virus responsible for an outbreak of encephalitis inof the West Nile virus responsible for an outbreak of encephalitis in the northeastern United States. The West Nile Virus outbreak of 1999 in New York: the Flushing hospital experience. Tularemia as a biological weapon: medical and public health manage-Tularemia as a biological weapon: medical and public health manage ment. Anthrax spores were accidentally released from in Exodus may have been anthrax in domesticated a military research facility located upwind from where animals followed by cutaneous anthrax in humans. According to the accounts provided Virgil described anthrax in domestic and wild animals by two Soviet physicians, 96 human anthrax cases in his Georgics, and anthrax was an economically im were reported, of which 79 were gastrointestinal and portant agricultural disease during the 16th through 17 cutaneous. Robert Koch established the microbial had occurred, and thus, inhalational anthrax may have 9,10 origin for anthrax in 1876. According to the Centers for Disease Control and Prevention, 22 people contracted 18,21-25 anthrax from the letters. The rapid detection/diagnosis, decontamination, and amount of funding budgeted to prepare and protect microbial forensics. Because of the ongoing terrorism the nation from a bioterror attack has rapidly increased threat, there has been a particular sense of urgency since 2001, and a significant amount of this funding has regarding the development and improvement of medi supported anthrax studies. Some of the new anthrax cal countermeasures, such as therapeutics, vaccines, studies have focused on improved sample collection, diagnostics, and devices. The spores are very resistant grows readily on sheep blood agar aerobically and is and may survive for decades in certain soil conditions. The organ veloped as research tools, have been incorporated into ism does not form spores in living tissue; sporulation the Laboratory Response Network established by the 46-49 occurs only after the infected body has been opened Centers for Disease Control and Prevention. Sporulation occurs the soil results from significant multiplication of the only when the organism in the carcass is exposed to air. The vast majority of these cases have disease occurs from contact with infected domesticated been cutaneous. Cases associated with industrial exposure, rarely 20th century, inhalational anthrax cases were reported seen now, occur in workers processing contaminated in rural villagers in Russia who worked with contami 64 hair, wool, hides, and bones. However, in taminated material leads to cutaneous disease, and recent years a significant decrease occurred in anthrax ingestion of infected meat leads to oropharyngeal or cases in domestic animals in east Russia. Inhalation of a suf tional anthrax cases occurred in woolen mill workers ficient quantity of spores, usually seen only during in New Hampshire in the 1950s. The largest reported played a major role in studying and defining anthrax, human anthrax epidemic occurred in Zimbabwe from as well as many other zoonotic diseases in wild and 1978 through 1980, with an estimated 10,000 cases. The role of toxins in virulence and immunity that strains cured of this plasmid no longer produced was firmly established by many researchers in the 76-78 the capsule and were attenuated, thus confirming the ensuing years. This strain was obtained dendritic cell function and appears to act with lethal 97 from a patient with symptoms similar to inhalational toxin to suppress the innate immune response. The possi bility of false positives from toxin-based identification tests should be considered because many diagnostic schemes have focused on toxin genes and gene prod ucts. It also appears occur in interstitial fluid or serum rather than on the 116 to promote apoptosis of endothelial cells lining the cell surface. Effects on hormone receptors, heptamer cleaved both a synthetic peptide substrate including glucocorticoids, have also been reported. Associated edema of the chest ing the entire face or limb, which is described by and neck may also be present. In addition, no age-related risk fac chemistry revealed the presence of B anthracis cell walls tor appears to be associated with cutaneous human and capsule antigens. Photographs: Courtesy of the Centers for Disease Control and Prevention, Atlanta, Georgia. Mortality had been essentially 100% in the absence of appropriate treatment; however, during 2001 the mortality rate was 45%. Meningitis with subarachnoid hemorrhage in a man from Thailand who died 5 days after eating undercooked Oropharyngeal and Gastrointestinal Anthrax carabao (water buffalo). Gastrointestinal anthrax Meningitis may occur after bacteremia as a compli 139 begins with nonspecific symptoms of nausea, vomit cation of any of the other clinical forms of the disease. Gram stain or culture of the lesion antibody tests are performed at Level D laboratories usually confirms the diagnosis. During the later stages of the disease patients develop sudden fever, dys pnea, diaphoresis, cyanosis, hypotension, shock, and 131 death. Blood culture should demonstrate growth in 6 to 24 hours if the patient has not received antibiotics before collection, and Gram stain of peripheral blood smears often reveals large bacilli in later stages of dis ease. Sputum examination is not helpful in making the diagnosis because pneumonia is usually not a feature of inhalational anthrax. Gastrointestinal anthrax is difficult to diagnose because of its rarity and nonspecific symptoms in cluding nausea, vomiting, anorexia, and fever. Diagnosis is usually considered only with a history of ingesting contaminated meat in the setting of an outbreak. Sore throat, dysphagia, hoarseness, cervical Diseases and the Defense Threat Reduction Agency/Threat lymphadenopathy, and edema as well as fever are Agent Detection and Response Program, National Center often presenting symptoms. The identifying the organism in cerebral spinal fluid by 131-133 early symptoms are nonspecific and include fever, microscopy, culture, or both. However, the development of respiratory anthrax cases and 67% to 94%145,146 of reported oropha distress in association with radiographic evidence of ryngeal anthrax cases. A positive skin test to anthraxin a widened mediastinum resulting from hemorrhagic (an undefined antigen derived from acid hydrolysis of mediastinitis and the presence of hemorrhagic pleural the bacillus that was developed and evaluated in the 147 effusion or hemorrhagic meningitis should suggest the former Soviet Union) has also been reported to help diagnosis. Contrast-enhanced computer tomography with the retrospective diagnosis of anthrax. Treatment should be anthracis possesses lactamase genes that may reduce 155-160 continued for 7 to 10 days, unless inhalational exposure the efficacy of this treatment. In addition, if a bioter 78 Anthrax rorism event occurs, the bacterial strains used may be Inhalational, oropharyngeal, and gastrointestinal intentionally antibiotic resistant or genetically modified anthrax should be treated with intravenous therapy to confer resistance to one or more antibiotics. The therapy should Tetracycline, erythromycin, and chloramphenicol initially include a fluoroquinolone or doxycycline with have also been used successfully161 for treating rare cases one or more of the following antibiotics: clindamycin, caused by naturally occurring penicillin-resistant organ rifampin, penicillin, ampicillin, vancomycin, amino isms. Additional antibiotics shown to be active in vitro glycosides, chloramphenicol, imipenem, clarithromy include gentamicin, cefazolin, cephalothin, vancomycin, cin, and linezolid. Experimental infections using the inhalational diseases severity and rapid onset. Recommendations mouse model have demonstrated significant efficacy for treatment during pregnancy and for pediatric 149,159 using these additional antibiotics. Annual doxycycline, and penicillin) beginning 1 day after boosters are recommended if the potential for exposure exposure to a lethal aerosol challenge with anthrax continues. Recent analysis has suggested imported from countries in which animal anthrax postexposure vaccination may shorten the duration of remains uncontrolled. People in direct contact and most effective strategy to counter a bioterrorism with potentially infected animals and laboratory event. This vaccine is no unusual rates of serious adverse events have been 177 made from sterile filtrates of microaerophilic cultures noted. Additional studies also support the safety of of an attenuated, unencapsulated, nonproteolytic strain the anthrax vaccine. These reactions peak at 1 to 2 days and cell-free culture supernatant from an attenuated, un usually resolve within 2 to 3 days after they peak. Systemic reactions are protection against cutaneous anthrax, with a lower characterized by flu-like symptoms, mild myalgia, 95% confidence limit of 65% effectiveness.
For example treatment herniated disc generic cytoxan 50mg with mastercard, in El-Mahalla El Kobra in the Gharbiya Governorate symptoms migraine order discount cytoxan, the rate of urbanization from 1950 to 1987 was 10 percent annually medicine and science in sports and exercise cytoxan 50mg cheap, but from 1987 to 1995 the rate shot up to 33 percent ayear medications or drugs cytoxan 50mg mastercard. Iran has the largest urbanized area in absolute terms in the region, followed by Saudi Arabia and Iraq, while the highest Urbanization Index is recorded for Gaza Strip, Bahrain, Palestine, Israel and Lebanon (Figure 13. Land sales also play an important role in the decline in the area of productive lands. Rainfed cultivation, which represented 89 percent of total cultivated land in 1983, had lost 22. Status of the Worlds Soil Resources | Main Report Regional Assessment of Soil Changes 409409 in the Near East and North Africa the main causes of soil problems in Jordan are: (i) improper farming practices, such as failure to use contour ploughing, or over-cultivation of the land; (ii) overgrazing; (iii) the conversion of rangelands to croplands in marginal areas where rainfall is insufcient to support crops in the long term; and (iv) uncontrolled expansion of urban and rural settlement at the cost of cultivable land. Urban populations are growing at 8 percent a year as opposed to just 1 percent in rural areas. Kuwait, 97 percent; Bahrain, 90 percent; Saudi Arabia, 83 percent; and United Arab Emirates, 84 percent). This high rate of urbanization has been accompanied by conversion of agricultural lands into urban areas. In Libya, over 25 percent of highly fertile lands have been taken over by the expansion of urban areas. An example of dramatic urban expansion is found in Lebanon where a study by Darwish and Khawlie (2004) showed that during the period from 1962 to 2000, urban areas expanded by 208 percent while agricultural lands decreased by 35 percent. Much of the area converted to settlements was highly productive agricultural land on Fluvisols, Luvisols and Cambisols. Some 32 percent of class 1 (prime land) and 26 percent of class 2 land were converted into urban areas. Status of the Worlds Soil Resources | Main Report Regional Assessment of Soil Changes 410410 in the Near East and North Africa 13. Main causes of soil degradation are: mismanagement coupled with poor policies; use of inappropriate technology; increased levels of trafc movements and road construction; industrial activities and mining; urban expansion; deforestation, overgrazing and inappropriate cultivation practices; and dumping of hazardous wastes. In this section, a link is made to the prevailing land uses in the diferent countries of the region, and the consequences and responses are discussed. The area afected by wind erosion in Iran is about 12 percent of the total country surface area, six times the global rate of 1. In the north-west of Yazd in the Yazd-Ardakan plain, total soil mass transported was measured at 220. This is due to various driving forces like poverty, lack of security and awareness, inadequate extension, absence of technical knowledge and fnancing. Elsewhere, driving forces for erosion processes were reported to be interrelated and to result in diferent degrees of degradation. In the El Bayadh region of Algeria, soils on limestone covers were classifed as moderately vulnerable, vulnerable and highly vulnerable to degradation as a function of their vegetation cover (Belaroui, Djediai and Megdad, 2014). The study describes how the Algerian steppe has in recentyears become the scene of an ecological and climatic imbalance. More generally in the southern part of the Mediterranean region, overgrazing and cultivation of vulnerable land in arid and desert regions have induced severe wind erosion. In Morocco, erosion is a serious agro environmental threat and was found to cause soil losses generally between 12 tonnes ha-1 yr-1 and 14 tonnes ha1 yr1. In some areas of the Rif Mountains these values reach 30 to 70 tonnes-1 ha-1 yr-1 (Benmansour et al. Using radioisotopes (137Cs), these authors found that the tillage process on sloping lands over the last half century had resulted in signifcant translocation of soils within the feld. The most important factors have been: increased population pressure on limited natural resources; over exploitation of forestry assets; removal of natural vegetation from sloping lands; overgrazing; cultivation of vulnerable lands in arid and desert regions; and inappropriate land management, mainly tillage practices. They also reported that water erosion accelerated by human intervention is the main cause in Morocco of soil degradation and of the deterioration of water quality that it entails. Soil erosion in Morocco afects up to 40 percent of its territory with the total annual soil loss evaluated at 100 million tonnes, equivalent to 50 million m3 annual reduction in dam storage capacity. Status of the Worlds Soil Resources | Main Report Regional Assessment of Soil Changes 411411 in the Near East and North Africa In El Bayadh region of Algeria, the Sirocco (a hot, dry wind blowing northwards from the Sahara) with a speed of 1. This area is threatened by yet more intensive erosion because of newly adopted government policies favouring extensive rainfed cereal cropping. In Tunisia, overall soil loss due to water erosion has been estimated to be equivalent to 23 000 ha yr-1 in the isohyets above 200 mm. In some areas of Syria, soil loss due to water erosion has been estimated to range from 10 to 60 kg ha-1 (under forest), from 200 to 2 550 kg ha-1 (under burned forest) and as high as 960 to 3 280 kg ha-1 (under agricultural land). Grazing and tillage practices generally contribute to vulnerability to water erosion. However, soil loss on tilled slopes can be one to four times that from grazed areas. Estimates of areas under serious water erosion in northern Iraq showed an increase from 12 percent in 1954 (Gibbs, 1954) to around 22 percent in 1997 (Hussein et al. The main reason was mismanagement of cropland and rangeland during the intervening four decades. In Yemen the surface runof to the sea measured in some major wadis is estimated at 1430 million m-3 yr-1 (Al-Hemiary, 1999). However, water erosion also occurs in the Badia region with its very low rainfall. The Badia soils are subject to water erosion because they are bare and highly exposed to what rainfall there is. The consequent formation of a slowly permeable seal and crust has enhanced runof and water erosion (Rawajfh, Khersat and Buck, 2005). However, farmers willingness to adopt conservation measures was infuenced by other factors too, including knowledge and perception, land tenure, and the type of landscape (Abu Hammad and Brresen, 2006). Some farmers in Lebanon are nonetheless reluctant to change their cultivation practices, particularly ploughing up and down slopes of more than 20 percent. Farmers are also expanding cultivation on steep slopes, even though they may be aware that this aggravates water erosion. They justify up and down ploughing as necessary for tractor performance, and steep lands are the only available land for extending cultivation (Zurayk et al. Status of the Worlds Soil Resources | Main Report Regional Assessment of Soil Changes 412412 in the Near East and North Africa In Sudan, studies showed that in areas afected by water erosion, about 74 percent of respondent households are exposed to food shortages that are sometimes severe (Akuot Gareng Apiu Anyar, 2006). In the coastal part of Sudan, although total annual rainfall is low (75 mm), the sandy texture of the soils makes them very highly erodible (Elagib, 2011). W ith the observed increasing seasonality and intensity of rainfall, high runof and erodibility in these areas could be expected to cause heavy soil degradation through soil loss. Studies on factors contributing to wind erosion in Sudan showed that in rainfed agricultural zones, deep ploughing and leveling of the surface soil caused an increase in its susceptibility to wind erosion, which, in turn, has led to a severe decline in its fertility and, in some places, to the formation of sand dunes. The fragility index (degraded land in ha divided by population) is a good measure of the extent of growing pressure in fragile ecosystems. Erosion caused by other land uses In Lebanon, increasing demand for construction materials has led to extensive unregulated mining activities, including a large number of open quarries. The high population density in countries like Kuwait (120 person km-2) has a profound infuence on soil disturbance through uncontrolled human activities. The Nabkha (stabilized aeolian landform developed as result of the deposition of wind-driven sediments around desert shrubs) along the coastal plain in Kuwait is used as a land degradation indicator (Khalaf and Al-Awadhi, 2012). The average annual sand drift rate in Kuwait is about 20 m3 (m width) 1 yr1 and negatively afects farms causing adverse environmental and economic impacts (Khalafa and Al-Jjimi, 1993). In the Jalal-Alzor (Kuwait), human activities such as the unregulated use of of-road vehicles has resulted in soil disturbance and accelerated soil erosion.
Treatment Short-term sedation: A 500micrograms/kg dose by mouth is often used to premedicate chil dren prior to anaesthesia medications in mothers milk cytoxan 50 mg. Continuous sedation: Some units give 60micrograms/kg/hour to sedate the ventilated baby medications ocd purchase 50mg cytoxan visa, but this strategy is now increasingly questioned symptoms ebola buy 50mg cytoxan amex. The rate of infusion must be halved after 24 hours in babies of <32 weeks postmenstrual age to prevent drug accumulation medications 2 cytoxan 50 mg mastercard. However, 300 micrograms/kg of the buccal preparation given into the nose or under the tongue will usually achieve this just as quickly (and this can be done outside hospital). Antidote All benzodiazepines cause hypotonia, hypotension and coma in excess, but these effects can be reversed by flumazenil, a competitive antagonist with a relatively short (50minute) half-life. Withdrawal symptoms in critically ill children after long term administration of sedatives and or analgesics: a first evaluation. Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial. Comparison of continuous drip of midazolam or lidocaine in the treatment of intractable neonatal seizures. Therapeutic options include dietary interventions (smaller, more fre quent feeds), positioning (elevating the head of the cot), drugs and, in extreme cases, surgery. Thickened formulae are increasingly being used to treat infants with reflux, driven in large part by the baby food industry. There is no good evidence, as yet, that this approach is of any value in reducing the apnoeic episodes attributed to reflux in the preterm baby. In some babies, it is important to exclude and treat cows milk protein allergy as the cause of the reflux (see web commentary). Milk thickeners A number of thickeners, designed to be added to the milk at the point of use, are available; rice cereal (more popular in North America), carob bean gum, carob seed flour, starches and sodium carboxymethylcellulose are often used. Care must also be taken to ensure that any products used are designed for use in babies and not older children. Carob seed flour is a galactomannan refined from the seeds of the carob (or locust) bean tree, Ceratonia siliqua. Cow & Gate (C&G) Instant Carobel (a similar product is marketed in some countries as Karicare Aptamil Feed Thickener) is made from carob seed flour. The powder also contains calcium carbonate, iron sulphate, zinc sulphate and maltodextrin. It is probably wise to monitor the red cell galactose-1-phosphate level in babies with known galactosaemia if using these products. Nestle Nestargel is a similar product (available in some countries) but which has less metabolis able carbohydrate and slightly more calcium carbonate. Although these products contain some carbohydrate, they do not add significantly (<1%) to the overall calories of the milk and thus do not replace a high-energy supplement if this is required. The product requires heat to thicken, so make up the infant formula and immediately add the Instant Carobel. A teat with a larger hole, for example, fast flow, will be required due to the increased thickness of the formula. Breastfeeding: Mix one scoop of Instant Carobel and 20ml warm, previously boiled water. Anti-reflux milks Anti-reflux formula milks are marketed by a number of different companies. As with the thickeners, the agent used to thicken these milks varies from company to company (see table). These milks are designed to meet the nutritional needs of otherwise healthy term babies and are not suitable for preterm infants. There is no evidence to suggest that any one of these formula milks is superior to any other. Supply Manufacturers are banned from subsidising the cost of infant formula milks supplied to hospitals or from providing free samples in an attempt to increase their share of the market with newly delivered mothers. The practice has been shown in nine controlled trials to reduce the number of mothers achieving a sustained lactation. Infant formula milks and modular feeds are a food source and therefore an excellent medium for bacterial and microbial proliferation. Powdered infant formula is a non-sterile product, and there is an inherent risk of infection with pathogenic bacteria such as Salmonella and Enterobacter sakazakii in preterm, low birthweight and immunocompromised infants who are most at risk. For this reason, most standard term and all preterm infant formula milks are available as ready-made bottles (for use in hospitals) and as either powder or ready-made in cartons for home use. Starch thickening of human milk is ineffective in reducing the gastroesophageal reflux in preterm infants: a crossover study using intraluminal impedance. The effect of thickened-feed intervention on gastroesophageal reflux in infants: systematic review and meta-analysis of randomized, controlled trials. Influence of nasogastric tubes on gastroesophageal reflux in preterm infants: a multiple intraluminal impedance study. The Special Feed Working Group of the Paediatric Group of the British Dietetic Association. Effects of thickened feeding on gastroesophageal reflux in infants: a placebo-controlled crossover study using intraluminal impedance. There is some evidence that combined short-term use with adrena line or dobutamine (q. A trial of long-term oral use in adults with heart failure in 1991 found an unexpected, and unexplained, increased mortality in those taking milrinone. An optimal response seems to be achieved when the blood level is ~200nanograms/ml. Mild thrombocyto penia is common when milrinone is infused for more than 24 hours. In animal studies, milrinone crosses the placenta, but there is no evidence of teratogenicity. There are no published reports relating to use during human pregnancy or lactation, and the manufacturers have not yet endorsed the use of milrinone in children. Treatment Population pharmacokinetic modelling in preterm infants suggests using a loading infusion of 0. Hypotension may occur while the loading dose is being given because the drug causes some vasodilation. Supply and administration 10ml ampoules containing 10mg of milrinone (as lactate) cost 19. The drug is stable in solution, so a fresh infusion does not need to be prepared every 24 hours. A population pharmacodynamic analysis of milrinone in pediatric patients after cardiac surgery. A prospective, double-blinded, randomized, placebo-controlled, interventional study. Neonatal persistent pulmonary hypertension treated with milrinone: four case reports. Nitric oxide and milrinone: combined effect on pulmonary circulation after Fontan type procedure: a prospective randomized study. Regulation of phosphodiesterase 3 in the pulmonary arteries during the perinatal period in sheep. Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease. Milrinone improves oxygenation in neonates with severe persis tent pulmonary hypertension of the newborn. Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxide. Randomised trial of milrinone versus placebo for prevention of low systemic blood flow in very preterm infants. Population pharmacokinetics and dosing regimen design of milrinone in preterm infants.
Cheap cytoxan 50 mg with amex. 5 Women Reveal How They Want Strangers To Approach Them.
Drugs with a large volume of distribution given before the start of hypothermia can be sequestered in peripheral tissues at the onset of hypothermia and may undergo recir culation upon re-warming treatment shingles buy cytoxan on line amex, exposing the patient to higher serum concentrations and a greater risk of toxicity medicine cabinets surface mount order cytoxan 50mg free shipping. It should not be forgotten that the baby undergoing therapeutic hypothermia will have symptoms thyroid problems generic 50mg cytoxan fast delivery, in many cases medicine during pregnancy order on line cytoxan, suffered hepatic and renal injuries and that this too can greatly impact on how the baby handles the drugs that are given. Table 4 lists most of the drugs that are used in asphyxiated infants undergoing therapeutic hypothermia; it explains where there is a known significant effect on that drugs efficacy due to altered metabolism. This list is not exhaustive but instead reflects merely those drugs in frequent use in this population and also those drugs for which information is available. Suggested dose adjustments Drug Effect of hypothermia during hypothermia Antibiotics Gentamicin Conflicting reports because of co-existing renal Give a dose of 4 mg/kg every injury. Penicillin and the pharmacokinetics of these antibiotics during No dose adjustment necessary other lactam hypothermia have not yet been studied, however, antibiotics because of their safe profiles, any effect, if there is one, is unlikely to be of any clinical significance. Anticonvulsants Phenobarbital Reduced clearance during hypothermia, some Give single loading dose of reports suggest a doubling of the half-life; however, 20 mg/kg this does not appear to have a clinically relevant effect. It exhibits non-linear (saturable) monitor levels metabolism via hepatic cytochromes P450 2C9 and 2c139 and levels are higher during hypothermia. Midazolam Midazolam is exclusively metabolized by hepatic Dosing not established in cytochromes P450 3A4 and 3A5. Clonazepam Clonazepam is metabolized extensively by Dosing not established in cytochrome P450 enzymes. Lidocaine Lidocaine is metabolised by hepatic cytochrome Use modified regime as suggested (lignocaine) P450 1A2 and 3A4. Topiramate Experience with topiramate in neonates is limited 5 mg/kg on the first day and then and pharmacokinetic data even more so. Very a lower dose (3 mg/kg daily) for limited data from infants undergoing hypothermia the next 2 days suggest a slower absorption and elimination. Continued 46 Effects of therapeutic hypothermia on medications Table 4 Continued Suggested dose adjustments Drug Effect of hypothermia during hypothermia Levetiracetam the predominantly renal excretion of Use modified regime as suggested levetiracetum should mean that hypothermia in levetiracetum monograph (q. Sedatives/analgesics Morphine There are potentially two effects of hypothermia on 50 micrograms/kg loading dose morphine to be considered; firstly, that the affinity over 30 minutes followed by an of morphine for the opioid receptors is reduced in infusion started at 10 micrograms/ hypothermia rendering it less effective, and kg/hour. Fentanyl Fentanyl is primarily metabolized by cytochrome Give a loading dose of 5 P450 3A4. Remifentanil Remifentanil has a short half-life due to rapid No data in neonates hydrolysis by non-specific blood and tissue esterases. Neuromuscular blocking agents Atracurium Atracurium is primarily metabolized by non No dose adjustment necessary. Effects of therapeutic hypothermia on medications 47 Table 4 Continued Suggested dose adjustments Drug Effect of hypothermia during hypothermia Pancuronium Pancuronium is primarily (~80%) excreted by the No dose adjustment necessary. Studies in the baby may seem to require hypothermic adults show an initial increased more frequent dosing to begin requirement during early stages of hypothermia with but once hypothermic the and then, when hypothermia is established, duration of action may be longer. Rocuronium In children undergoing hypothermia for a variety No dose adjustment necessary. Vercuronium Vecuronium is primarily eliminated via the liver by No initial dose adjustment is carrier-mediated transport (via p-glycoprotein) and necessary but titrate the dose P450-mediated metabolism. Inotropic agents Adrenaline There is no evidence to suggest that a different No dose adjustment necessary. Titrate according to response Milrinone There is very limited data regarding milrinone in No dose adjustment thought to therapeutic hypothermia. Abstracts and some of the articles and updates of this version appear are available free of charge, otherwise a annually. Relatively few peri involved in the delivery of perinatal natal issues are covered, but the number care. Regularly development of neonatal guidelines and updated full text is available on the web. It is semi international not-for-profit organisation continuously updated and published whose aim is to provide up-to-date afresh in book form every 6 months, but information about the effects of health Neonatal Formulary 7: Drug Use in Pregnancy and the First Year of Life, Seventh Edition. The library contains the Cochrane Contraception Database of Systematic Reviews, the the website managed by the Faculty of Database of Abstracts of Reviews of Sexual and Reproductive Healthcare (for Effectiveness, and the Cochrane Central merly the Faculty of Family Planning and Register of Controlled Trials. Access to Reproductive Health Care) in the United the full text of all the reviews that have Kingdom provides authoritative advice something useful to say about drugs on all aspects of contraception and family mentioned in the main section of this planning. It is also an essential requirement if the results are to be pub Communicable disease lished in many journals. Information centres about trials is now becoming available Many countries maintain a national through a number of sites listed below. The site provides can also offer help to those who want to data on maternal and infant levels of drugs, contact other families facing a similar possible effects on breastfed infants and on challenge. The Kingdom provides a website giving Trust offers freely available evidence information on drug interactions. It also offers register Online Mendelian Inheritance in advice on travel vaccinations and travel Useful websites 51 issues. The website provides extensive neonatal-nurses-association regularly updated information on all issues Australian College of Neonatal Nurses relating to childbirth. The site pro and Care Excellence vides links to areas designed for mothers this organisation was originally set up in and professionals as well as a specific site 1999 as the National Institute for Clinical for foetal alcohol syndrome research. The website has separate sections on patient and public involvement, medicines and Royal College of prescribing and guidance development. The British Association of Perinatal Medicine has Neonatology on the Web also issued a number of important guide this site contains an absorbing selection lines. The most recent (fifth) edition Two large collaborative groups collate was published in 2007. An outline sum information and disseminate advice on mary of its current advice on individual drugs that may be teratogenic. It also provides a cross link to vance, efficacy and safety, and comparative all relevant Cochrane Reviews. The staff should never prescribe or administer any drug without first familiarising themselves with the way it works, the way it is handled by the body and the problems that can arise as a result of its use. Such dosage tables can be a useful aide-memoire, but they should never be relied upon, on their own, to help the staff decide what to use when, what works best or what potential adverse effects are commonly encountered during use in infancy. In addition, lists summarising common side effects and potential drug interactions are seldom of much help in identifying which problems are common or likely to be of clinical importance in the neonate, and access to this more detailed information is as important for the staff responsible for drug administration as it is for those prescribing treatment in the first place. Never use anything except the most recent edition of this or any other reference text. Indeed, copies of earlier editions should not be left where they might get used in error. Acetylcysteine (n-Acetylcysteine) Use Acetylcysteine is the first-line therapy for paracetamol overdose in all age groups. There are also a number of avenues of research where acetylcysteine use is being explored as a means of reducing oxidative stress in patients of all ages; the results of these studies, however, merit further scrutiny before acetylcysteine can be recommended. Background Acetylcysteine is the N-acetyl derivative of the amino acid L-cysteine and is a precursor in the formation of the antioxidant glutathione.