Hani Jneid, MD

• Division of Cardiology
• Massachusetts General Hospital
• and Harvard Medical School
• Boston, Massachusetts

Coats disease is characterized by an exudative retinal detachment caused by leaky congenital vascular anomalies in the retina spasms after gall bladder removal generic voveran 50mg fast delivery. Histopathologically, the retina contains abnormal telangiectatic vessels, and its outer layers are massively thickened by hard exudates spasms after surgery 50mg voveran amex. A bullous retinal detachment may abut the lens, displacing it anteriorly and causing pupillary block glaucoma spasms 7 weeks pregnant order voveran 50mg mastercard. What are the characteristic features of persistent hyperplastic primary vitreous (persistent fetal vasculature) Leukocoria is caused by a plaque of fibrovascular tissue that adheres to the posterior surface of the lens spasms translation cheap 50mg voveran with visa. The ciliary processes typically are disclosed by dilating the pupil because their tips are attached to the edge of the retrolental plaque and drawn centrally spasms kidney stones generic voveran 50 mg visa. Embryonal medulloepithelioma is the second most common primary intraocular tumor of childhood muscle relaxer kidney generic 50mg voveran visa. Medulloepitheliomas probably are derived from anlagen of the embryonic medullary epithelium, which lines the forebrain and optic vesicle. Most of these rare tumors become symptomatic around age 4 years and are diagnosed at 5 years of age. Most medulloepitheliomas are ciliary body tumors that arise from the neuroepithelial layers on their inner surface. In addition to bands, cords, and rosettes of neoplastic neuroepithelium and pools of hyaluronic acid, teratoid medulloepitheliomas contain foci of heteroplastic tissue including hyaline cartilage, rhabdomyoblasts, striated muscle, and/or brain. Orbital capillary hemangioma (hemangioma of infancy) should be treated only if there is evidence of: & Amblyopia caused by refractive error (induced myopia or astigmatism) or & Ptosis causing visual obstruction or head tilt. In children, consider: & Ruptured dermoid cyst, which causes a fulminant soft tissue inflammation & Rhabdomyosarcoma & Lymphangioma, especially with rapid expansion from a blood-filled ``chocolate cyst' & Neuroblastoma, which can present with a rapid onset of proptosis and ecchymosis In adults, consider: & Ruptured dermoid cyst & Lymphangioma & Extrascleral spread and necrosis of an intraocular melanoma & Metastatic disease to the orbit 3. Not only are the lesions distinct histopathologically, but also cavernous hemangioma is a slowly proliferating entity. Because of its slow growth, it is usually a well-tolerated lesion that causes few symptoms. Fibrous histiocytoma & Fibrous histiocytoma is the most common mesenchymal tumor that afflicts adults. Hemangiopericytoma & Hemangiopericytoma has reclassified as solitary fibrous tumor with cellularity. In other words, a histologically benign lesion may behave aggressively and recur after excision, whereas a tumor with aggressive features on microscopic examination may never recur. The A pattern is characterized by abundant, tightly packed spindle cells, whereas the B pattern exhibits fewer cells within a myxoid matrix. Occult metal within the magnetic field can move and cause severe soft tissue damage. Embryonal & this group is further subdivided into classic, botryoid, and spindle cell. Much of what is known about the treatment of orbital rhabdomyosarcoma comes from the four Intergroup Rhabdomyosarcoma Studies. Unilateral or bilateral proptosis usually requires imaging, especially if it is progressive. Well-tolerated, well-circumscribed lesions of the orbit can be followed conservatively with serial imaging alone in selected cases. The final rule is important clinically, because a basaloid histopathology for adenoid cystic carcinoma carries the worst prognosis. The incidence of infectious and noninfectious inflammatory dacryoadenitis is several times higher than in an orbital referral practice. What factors help to distinguish benign and malignant epithelial lacrimal gland tumors What is the most common metastatic tumor to the orbital soft tissue in men and women Otherwise, prostate carcinoma would be an acceptable alternative in men, depending on the clinical series. Note: Metastatic lesions are approximately 10 times more common to the uvea than the orbit on autopsy studies. This may be caused by the high blood flow through the choroid, which may allow more facile metastatic seeding of uveal tissue. Regardless of the histopathology, any lymphoproliferative lesion of the orbit or ocular adnexa requires a systemic work-up, as follows: & Complete blood count is performed. The latter occurred in a village near the Ebola River, from which the disease takes its name. This is because wild type-2 strains are already eradicated and not circulating in the community since 1999. Manifestations Most human coronaviruses are widespread affecting people of most part of the world and produce mild respiratory tract infection. Outbreak had spread from Asia to various region of the world causing about 8,098 probable cases including 774 deaths from 2002 to 2003. Source- Though the source is unknown, but it would have acquired animals such as camels and bats. Clinical manifestation- - Severe acute respiratory illness with symptoms of fever, cough and shortness of breath. Some people develop gastrointestinal symptoms including diarrhea and nausea/vomiting. I Filtration Excellent way to reduce the microbial population in solutions of heat-labile materials- like vaccine, antibiotics, toxin, serum and sugar. Typhi in a given time divided by the dilution of phenol which sterilizes the suspension in the same time. Animal waste (animal tissues, organs, body parts carcasses, bleeding parts, fluid, blood and experimental animals used in research, waste generated by veterinary hospitals/ colleges, discharge from hospitals, animal houses). Microbiology and biotechnology waste (wastes from laboratory cultures, stocks or specimens of micro-organisms live or attenuated vaccines, human and animal cell culture used in research and infectious agents from research and industrial laboratories, wastes from production of biological, toxins, dishes and devices used for transfer of cultures). Category No 1 Category No 2 Category No 3 25 Review of Microbiology and Immunology Waste Category Waste sharps (needles, syringes, scalpels blades, glass etc. Discarded medicines and cytotoxic drugs (wastes comprising of outdated contaminated and discarded medicines). Solid waste (items contaminated with blood and body fluids including cotton, dressings, soiled plaster casts, line beddings, other material contaminated with blood). Solid waste (disposable items other than the waste sharps such as tubing, catheters, intravenous sets etc. Liquid waste (waste generated from laboratory and washing, cleaning, house-keeping and disinfecting activities). Chemical waste (chemicals used in production of biological, chemicals, used in disinfection, as insecticides, etc). Which of the following is used to test the efficiency of sterilization in an autoclave Choose the correct ones for the decreasing order of resistance to sterilization: a. Disinfection of water by routine chlorination is classified under: (Karnataka 2005, 07) a. To make instrument safe for use in the next patient, most appropriate method to disinfect the endoscope is by: a. The resident doctor who changed his dressing the next day found it to be soaked in blood. Pour 1% hypochlorite on the dressing material and send it for incineration in appropriate bag b. I Pour-Plate Culture Used to quantitate bacteria in urine cultures I Stab Culture Stab culture is used for maintaining stock cultures. Recommended transport medium for stool specimen suspected to contain enteric pathogens is: a. Lysogenic conversion: Bacteriophage when integrated with the bacterial chromosome, this stage is called as lysogenic conversion. Detect genetic diseases such as sickle cell anemia, phenylketonuria, and muscular dystrophy. The following phenomenon is responsible for antibiotic resistance in bacteria due to slime production: a. D alanyl-D alanine gets altered to D alanyl-D lactate which has less affinity for Vancomycin. I Chromosome coding for Immunoglobulin Chains Heavy chains By chromosome -14 Light chain kappa By chromosome -2, Light chain lambda By chromosome -22 56 Antigen, Antibody and Antigen Antibody Reaction, Complement. All of the following interaction occurs between antigen antibody reaction except: (Recent Question 2013) a. These result due to subtle amino acid changes resulting from allelic differences Review of Microbiology and Immunology b. These result due to changes in amino acid in heavy and light chain at variable region Changes in heavy and light chain in constant region is responsible for class and subclass of immunoglobulins these are areas in antigen that bind specifically to antibody 26. Which of the following is associated with class specific antigenic determinants of an immunoglobulin Which antibody deficiency causes recurrent infection by organisms with polysaccharide capsule Which of the following statements is true regarding kappa, lambda and heavy chain immunoglobulins Recurrent facial/oropharyngeal /laryngeal edema in a patient has low C4 & C3 and normal factor B. Which of the following best denotes classical complement pathway activation in immuno inflammatory condition: a. Due to antigen cross reactivity between them, antibody response against cow pox vaccine can protect against small pox. When antigen comes and binds to fab region of IgE, it in turn stimulates mast cell and mast cell degranulation occurs. Fluorescence detected by fluorescence microscope Luminometer detection Scintigraphy by gamma camera Section:2- Immunology 57. Targets and Effects Vasculature (inflammation); hypothalamus (fever); liver (induction of acute phase reactant proteins) Contd. Which of the following chemical mediators of inflammation isanexampleofaC-X-Coralphachemokine Hence the progenitor T cells undergo positive selection followed by negative selection to delete the self reacting T cells. Hence, during embryonic life, the negative selection of the self reacting B cell clones is sufficient for deletion of self reacting clones. Injection of ovalbumin in rabbit induces production of which of the following antibody After few years, brother to sister skin transplant was done, but rejection occurred. In a post operative ward, 4 out of 10 patients developed wound discharge, which on culture was found to be positive for coagulase positive gram positive cocci. On surveillance cultures, a health care personnel attending to the patients was found to be a nasal carrier for the same agent. It will be sensitive to treatment with antibiotics containing amoxicillin+ clavulinic acid combination. A patient has prosthetic valve replacement and he develops endocarditis 8 months later. A person had infection due to gram positive organism treated with methicillin and then culture sensitivity shows resistance to it. A majority of infections caused by coagulase- negative Staphylococci are due to Staphylococcus epidermidis b. Methicillin resistance in Staphylococcus aureus is independent of -lactamaseproduction b. His blood culture shows growth of gram positive cocci which are Catalase positive and coagulase negative. Food poisoning after 1-5 hr of consumption of ice cream, identify the causative agent A 25 year old female presented to the hospital on the third day of menstruation with complaints of high fever, vomiting and a rash on her trunk and extremities. Fibrinolysin (activate plasminogen) Rapid spread- By preventing the formation of fibrin barrier. D-Alanine D-Alanine side chain of peptidoglycan layer is altered to D-Alanine D-Serine or D-Alanine D-Lactate) and this altered side chain has less affinity for vancomycin S.

Waste management practices must meet national and local requirements; the following principles are recommended as a general guide: Principles of waste management Develop a waste management plan that is based on an assessment of the current situation and which minimizes the amount of waste generated spasms jaw muscles purchase voveran from india. Segregate clinical (infectious) waste from non-clinical waste in dedicated containers muscle relaxant cvs voveran 50mg overnight delivery. Sharps containers should be made of plastic or metal and have a lid that can be closed muscle relaxer ketorolac buy voveran online now. Biohazard Symbol Identify a storage area for waste prior to treatment or being taken to final disposal area spasms kidney area purchase voveran uk. Treatment of hazardous and clinical/infectious waste Each health care facility should identify a method for the treatment of clinical/infectious waste muscle relaxant starting with b buy voveran 50mg line. This may consist of transportation of infectious waste to a centralized waste treatment facility or on-site treatment of waste spasms on left side of body purchase voveran 50 mg with mastercard. If neither method is available, chemical treatment with 1% hypochlorite or a similar disinfectant is recommended. However, excessive use of chemical disinfectants should be avoided as it may be a health and environmental hazard). If this is not possible, contaminations should be removed by manual washing, ensuring adequate personnel and environmental protection. The classification of risk of transmission of infection by instruments and equipment has been called the "Spaulding Classification" 8. The risk of transmission is classified according to the site where the instrument is to be used. Contact sites for instruments may be classified as critical, semi-critical or non-critical. The level of reprocessing required is based on the classification and level of risk. Any instrument or equipment entering into a sterile part of the body must be sterilized. Where the instrument or equipment will be in contact with mucous membranes or non-intact skin, it must have undergone disinfection, and where there will be contact with intact skin, disinfection or cleaning should be used. Level of disinfection/cleaning required for patient care equipment2,3,8 Application SpauldingClassification Level of risk High Level of reprocessing required Sterile Examples Storage of reprocessed instrument Sterility must be maintained. Into vascular system Into sterile cavity Into sterile tissue Surgical procedure, Sterilization by entry into steam under sterile tissue, pressure or an automated low-temp arthroscopy, biopsies, chemical sterilant system, other liquid intravascular chemical sterilant or cannulation ethylene oxide sterilization. Respiratory therapy, gastroscopy Intact skin, no contact with the patient Non-critical Low Beds, sinks, etc. Store in a clean dry place 28 Practical Guidelines for Infection Control in Health Care Facilities 1. Staff Training Staff who work in the sterilizing service department and are responsible for the reprocessing of instruments and equipment must have undergone formal training in how to clean, disinfect and sterilize instruments and equipment. The level of training must be appropriate for the level of responsibility that the staff member is expected to undertake. Appropriate Level of Reprocessing As described above it is essential that the correct level of reprocessing of an instrument/equipment is chosen according to its intended use. This decision is made not according to what the instrument or equipment is, but rather what it is intended use is. Steam sterilization is recommended as the most effective method to achieve sterility. However, this may not always be possible as some instruments may not be able to withstand the temperature or moisture required for sterilization using steam. Other methods may be used to achieve sterility such as ethylene oxide or automated low temperature chemical sterilant systems, provided the manufacturer of the instrument / equipment agrees that this is an effective means to sterilize them. Servicing of instruments and equipment Prior to sending medical devices for service they should be reprocessed appropriately. If however they are unable to be reprocessed before being repaired, they should be placed in a fluid resistant plastic bag or container and labelled appropriately before being sent for repair. Instruments and equipment like these may not be able to withstand the heat or the moisture of steam or thermal disinfection or even some chemical agents. It is essential that equipment that will not withstand the regular types of Environmental Management Practices 29 reprocessing must only be reprocessed in a department that has the proper facilities. Storage Storage of instruments and equipment is an essential component in ensuring the product maintains its level of sterilization or disinfection. Most instruments and equipment are dry and packaged once they have been sterilized. Correct storage of sterile instruments and equipment is a critical component in keeping them sterile. Patient care equipment Any equipment that is used for a patient, and touches only their intact skin, such as bedpans, urinals, commode chairs, blood pressure cuffs etc. If not cleaned properly, organic matter may prevent the disinfectant or sterilant from having contact with the instrument/equipment and may also bind and inactivate the chemical activity of the disinfectant. After an instrument has been used, prior to it drying, it should be washed to remove any gross soiling. Manual cleaning All surfaces of the instrument/equipment must be cleaned taking care to reach all channels and bores of the instrument. Enzymatic cleaners Used for fibreoptic instruments and accessories, and other items that are difficult to clean. Ultrasonic cleaners and automated washers Ultrasonic cleaners and automated washers are recommended for cleaning basic instruments that can withstand this process. Using a machine to wash the instruments will cut down on the handling of the instruments. By causing high frequency, high-energy sound waves to hit the instrument/equipment, the soiling matter drops off the instrument, or becomes easy to remove during the rinsing process. These cleaners are not appropriate for use on cannulated instruments (they cannot clean inside the instrument), plastic materials, two or more different metals, or some glass instruments, syringes and lenses. Disinfection is used to destroy organisms present on delicate or heat-sensitive Environmental Management Practices 31 instruments which cannot be sterilized or when single use items are not available. Disinfection is not a sterilizing process and must not be used as a convenient substitute for sterilization. Thermal disinfection is not appropriate for instruments that will be used in critical sites (see Table 1) as these instruments must be sterile. These levels are classified as:2,3 (a) High-level disinfection: Destroys all micro-organisms except some bacterial spores (especially if there is heavy contamination). Thermal disinfection (pasteurization) If an instrument is able to withstand the process of heat and moisture and is not required to be sterile, then thermal disinfection is appropriate. By using heat and water at temperatures that destroy pathogenic, vegetative agents, this is a very efficient method of disinfection. The level of disinfection depends on the water temperature and the duration the instrument is exposed to that temperature. Minimum surface temperature and time required for thermal disinfection3 Surface Temperature (oC) 90 80 75 70 Minimum disinfection time required (minutes) 1 10 30 100 32 Practical Guidelines for Infection Control in Health Care Facilities 2. Chemical disinfection the performance of chemical disinfectants is dependent on a number of factors including: temperature, contact time, concentration, pH, presence of organic or inorganic matter and the numbers and resistance of the initial bioburden on a surface. Only instrument grade disinfectants are suitable to use on medical instruments and equipment. Hospital grade or household grade disinfectants must not be used on instruments, they are only suitable for environmental purposes. It is important that it is stored correctly and according to the manufacturers instructions. Glutaraldehyde is generally the most appropriate chemical disinfectant that will provide high-level disinfection. This chemical must be used under very strict controlled conditions and in a safe working environment. Environmental Management Practices 33 Glutaraldehyde 2% is an appropriate high level disinfectant for endoscopes, respiratory therapy equipment and for material that is destroyed by heat. Flexible endoscopes are very easy to damage and particularly difficult to disinfect. It is extremely important that meticulous mechanical cleaning must always precede sterilization or disinfection procedures. Before any instrument or equipment goes under the process of steam sterilization, the following should be checked: (1) Ensure that the instrument can withstand the process. Instruments and equipment will only be sterile if one of the following sterilizing processes is used: (1) Steam under pressure (moist heat), (2) Dry heat, (3) Ethylene oxide, (4) Automated environmentally sealed low-temperature peracetic acid, hydrogen peroxide plasma and other chemical sterilant systems or sterilants, or (5) Irradiation. Steam under pressure (moist heat) sterilization3 this is the most efficient and reliable method to achieve sterility of instruments and equipment. There are several types of steam under pressure sterilizers (also called autoclaves): Downward (gravity) displacement sterilizers (jacketed and non-jacketed) - these are designed for the sterilisation of waste, solutions and instruments. Benchtop sterilizers do not take wrapped items and therefore items must be used immediately after they are removed from the sterilizer. There will be differences in the models and types of features that are offered may vary. These variations may include: drying stage, ability to take packaged and unwrapped items, systems to monitor temperature, pressure and holding time. Dry heat sterilization3 Dry heat sterilisation is caused by hot air that destroys pathogens by the process of oxidation. Dry heat sterilizes have had limited value because it is difficult to maintain the same temperature throughout the load, while the high temperatures and long time required to achieve sterility makes this method undesirable for many situations. The time required to process the instrument is Environmental Management Practices 35 dependent on the temperature, humidity and concentration level of the gas. The gas must penetrate the packaging and reach all surfaces of the instrument/equipment requiring sterilization. Automated chemical (low temperature) systems3 Hydrogen peroxide plasma in a fully automated cycle can achieve low temperature, low moisture sterilization within a 45-80 minute cycle depending on the model of sterilizer used. Irradiation Gamma radiation is available from some commercial gamma irradiation facilities. Only those instruments and equipment that have undergone the entire sterilizing process can be regarded as sterile. It maintains sterility for a long period, can act as a sterile field and can also be used to wrap dirty devices after the procedure. Regular engineering maintenance on sterilization equipment must be performed and documented. Boiling of medical devices for reuse is not recommended since it does not guarantee sterility. However, in certain resource-poor situations where steam sterilization is not possible, these items should be thoroughly cleaned and subjected to a cycle in a pressure cooker for 30 minutes. Iatrogenic transmission has been observed in some patients who have been recipients of contaminated human growth hormone, gonadotropin and corneal, pericardial and dura mater grafts. If material has been contaminated with prions or contamination is suspected the preferred method is steam sterilization for at least 30 minutes at a temperature of 132oC in a gravity displacement sterilizer. If a prevacuum sterilizer is used, 18 minutes at 134oC has been found to be effective. Semi critical and non-critical items may be immersed in 1N sodium hydroxide, a caustic solution, for 1 hour at room temperature and then steam sterilized for 30 minutes at a temperature of 121 oC. Toilets / bathrooms - may be used in place of liquid bleach if this is unavailable Smooth metal surfaces, tabletops and other surfaces on which bleach cannot be used. Detergent with enzyme Cleaning endoscopes, surgical instruments before disinfection is essential Note: A neutral detergent and warm water solution should be used for all routine and general cleaning. Standard procedure for cleaning and disinfection of various reusable equipment is provided in Table 7.

For example, a subject who ingested about 50 mL of nitrobenzene, as reported by Myslak et al spasms to the right of belly button discount voveran 50 mg online. These reached maximum levels on day 2 for p-aminophenol (198 mg/day) and on day 3 for p-nitrophenol (512 mg/day) muscle relaxant menstrual cramps cost of voveran. Their results demonstrated that urine was a major excretion pathway, with 45% of the radioactivity following a [14C]-nitrobenzene dose excreted in urine within 72 hours spasms icd 9 code discount 50mg voveran amex. Parke (1956), using [14C]-nitrobenzene, was able to demonstrate in rabbits that 0 spasms while eating cheap 50mg voveran overnight delivery. Samples of feces, urine, and expired air were collected at various time points up to 72 hours muscle relaxant breastfeeding buy voveran us. Urinary metabolites of nitrobenzene were identified after incubation with -glucuronidase and/or sulfatase xanax muscle relaxer buy cheap voveran line. The disposition of radiolabeled products among feces, urine, and expired air 72 hours after dosing is shown in Table 3-6, corroborating urine as the primary route of excretion in all exposed groups. Species and strain differences were evident in the degree of conjugation exhibited by nitrobenzene metabolites (Table 3-7). In F344 rats, all nitrobenzene metabolites were conjugated as sulfates, confirming the observation of Levin and Dent (1982). Albrecht and Neumann (1985) administered a single dose of 25 mg/kg nitrobenzene by gavage to female Wistar rats. They found that 50% of the dose was eliminated via urine within the first 24 hours and a total of 65% of the dose was excreted in urine within 1 week. Urinary excretion of nitrobenzene metabolites in male rats and mice gavaged with a single oral dose of [14C]-nitrobenzene Percentage of dosea Free/ conjugate Free Glucuronide Sulfate Free Glucuronide Sulfate Free Glucuronide Sulfate Free Glucuronide Sulfate Total Total F344 rat (mg/kg) 225 22. However, a number of case reports of nitrobenzene poisoning have been published in the biomedical literature. As described in the following sections, nitrobenzene induces a suite of well-characterized toxicological responses irrespective of the route of exposure-oral, inhalation, or dermal. Some toxicokinetic information on nitrobenzene has also emerged from studies in which nitrobenzene was administered to human research subjects (see section 3). Upon arrival, the patient was cyanotic, and his respiration was shallow and irregular. Blood was obtained and was dark brown in color, and methylene blue was administered. The patient underwent seven blood transfusions, after which the level of metHb in the blood gradually declined. Five days after admission, the patient continued follow-up for a mild poison-induced hemolytic anemia. The resulting acute symptoms of toxicity included cyanosis, unconsciousness, and severe methemoglobinemia (82% about 90 minutes after consumption of nitrobenzene), and the patient initially had a distinct smell of bitter almonds on the expired breath. This report is typical of accounts in which subjects have experienced nitrobenzene-induced toxicosis through consuming nitrobenzene-containing substances. Harrison (1977) described the case of a 19-year-old male who consumed a brown liquid while pipetting that apparently contained nitrobenzene. Ascorbic acid infusion results in acidosis and a resultant shift of the oxygen dissociation curve to the right, which improves oxygen delivery to the tissues. Profound signs of methemoglobinemia were associated with an initial metHb level of 65% and the characteristic chocolate brown coloration of the blood. The patient underwent gastric lavage and received intravenous administration of methylene blue, ascorbic acid, methylprednisolone, and diazepam. Following blood transfusions, the patient ultimately had an uneventful recovery and was discharged after 19 days. The characteristic signs of acute nitrobenzene poisoning (coma, cyanosis, a smell of bitter almonds on the breath) were evident in a 24-year-old female who had ingested an unreported quantity of nitrobenzene (Ajmani et al. As in other cases, the patient was responsive to a treatment protocol featuring gastric lavage, intravenous fluids, methylene blue, ascorbic acid, and diuretics. During day 6 of the recovery phase, the subject developed mild jaundice and anemia, yet fully recovered within 2 weeks. On arrival, the patient was in a deeply comatose state with very shallow breathing. Blood samples were obtained that were dark brown in color, and a diagnosis of methemoglobinemia was made, secondary to nitrobenzene consumption, when there was no change in the blood sample color after it was placed on white filter paper and bubbled with oxygen. Gastric lavage was performed, and ascorbic acid and methylene blue were administered intravenously. A range of clinical manifestations was observed in affected subjects, including vomiting, dizziness, cyanosis (oral, distal, or general), respiratory depression, convulsions, and generalized weakness. Nuclear magnetic resonance and infrared spectroscopy were used to analyze the almond oil samples and positively confirmed the presence of nitrobenzene. The patient showed an initial improvement as a result of gastric lavage and oral administration of vitamin C (methylene blue was not given in this case). Table 4-1 presents a chronological compilation of the cases reported in this section. However, no case reports were identified that addressed the toxicity of nitrobenzene solely via the inhalation route. For example, the incident described by Ikeda and Kita (1964) most likely also involved dermal contact (section 3. The patient presented with a range of typical symptoms of nitrobenzene toxicosis, including headache, nausea, weakness, hyperalgesia, and cyanosis. The woman had been employed for 17 months in a small paint firm where she painted and polished lids of pans with a red paint containing nitrobenzene as a solvent. The patient started to complain of severe headache, nausea, vertigo, and numbness in the legs approximately 2 months later. Nearly 3 months later, the patient experienced the same bout of symptoms, and she was admitted to the hospital the following day. Cases of human poisoning following ingestion of nitrobenzene Subject(s) Male, 5 years Agent, dose Screen-printing material, unknown quantity Unknown substance, unknown quantity Nitrobenzene, unknown quantity Bitter almond oil, unknown quantity Symptoms Methemoglobinemia; cardiac arrest and death after initial improvement Shock, cyanosis, tachycardia, 41% methemoglobinemia Cyanosis, labored breathing, tachycardia Vomiting, dizziness, cyanosis, respiratory depression, convulsions, methemoglobinemia Coma, dark brown blood Coma, cyanosis, bitter almond breath, mild jaundice Treatment Gastric lavage, ascorbic acid Methylene blue Reference Gupta et al. Dermal Exposure A number of case reports exist in which at least a portion of the nitrobenzene dose was absorbed via the dermal route. For example, Stevens (1928) discussed a case in which infant twins were exposed to nitrobenzene contained in a disinfectant that had been applied to their mattress to exterminate bed bugs. The subjects displayed marked cyanosis, rapid pulse rates, and depressed respiration rates, and blood samples revealed the presence of methemoglobinemia. Both subjects made a steady recovery when removed from the source of the contamination. Levin (1927) discussed the case of a 2-year-old child who was dermally exposed when his mother painted his shoes with a dye containing nitrobenzene. Cyanosis ensued, with rapid pulse and depressed respiration, similar symptoms to those of the infant twins described by Stevens (1928). A sample of blood was extremely dark in color, though metHb was not measured 29 specifically. With the aid of bed rest and occasional oxygen administration, the child recovered once the source of the poisoning had been removed. Zeligs (1929) reported similar cases involving infants who had been dermally exposed to nitrobenzene or aniline from a laundry mark that had been stamped on their cotton mattress pads. They recovered rapidly when oxygen was administered to aid the restoration of oxyHb levels. As with the other early cases, it is not clear whether exposure was via inhalation, dermal, or both routes. The patient presented with marked cyanosis and methemoglobinemia, considerable temperature fluctuations, and the appearance of a skin rash. The infant recovered steadily with the aid of oxygen, an intravenous injection of 5% dextrose, and two blood transfusions. A paper by Zeitoun (1959) discussed 21 cases of cyanotic infants and children who had become sick after being rubbed with fake bitter almond oil that contained nitrobenzene. As in other cases, a range of symptoms including hypoxia, weakness, shock, and, in some cases, excitation or depression accompanied profound methemoglobinemia. Of the 21 cases, 2 subjects died from complications associated with developing bronchopneumonia, while the remaining 19 subjects recovered completely. A more recent example of methemoglobinemia induced through dermal penetration of nitrobenzene occurred in a 2-month-old baby boy whose mother rubbed his skin with Oleum dulcis, a topical hair oil containing about 1% nitrobenzene (Mallouh and Sarette, 1993). The typical presentation of bluish coloration of the skin and lips was accompanied by a chocolatecolored venous blood sample, in which the metHb level reached 31. A chronological compilation of the case reports involving inhalation and/or dermal exposure to nitrobenzene is presented in Table 4-2. Cases of human poisoning with nitrobenzene following inhalation or dermal exposure Subject(s) Male, 2 months Agent Dermal application of O. The doses selected were based on the outcome of a 14-day range-finding study in which 10 animals/sex/group received doses from 37. In the range-finding study, all rats and mice receiving 600 mg/kg-day and all rats and a single mouse receiving 300 mg/kg died prior to planned termination. Toxicological responses to nitrobenzene among 31 the survivors in the range-finding study included depressed body weight gain that was evident in male mice receiving 37. Other toxicological endpoints included statistically significant increases in reticulocyte counts 7 and metHb levels. These responses exceeded control levels in treated rats (doses not specified), in male mice at 75 mg/kg and above (reticulocytes) and 150 mg/kg and above (metHb), and in female mice at 75 mg/kg and above (metHb). Histopathologic lesions were observed in brain, liver, lung, kidney, and spleen in rats and mice, though at unstated dose levels. In the main study, all animals were observed twice daily for clinical signs of toxicity, and body weights and food consumption were monitored weekly. Blood samples were obtained at term to measure hematologic parameters, reticulocyte count, and metHb levels, and the weights of the brain, liver, right kidney, thymus, heart, lungs, and right testis were recorded. Necropsies were performed on all animals that died prematurely or were sacrificed at term, and gross examinations of a large suite of organs and tissues were carried out. Tissues were preserved in formalin, and most of those listed were processed for histopathologic examination, primarily all controls, rats at 75 and 150 mg/kg-day, and mice at the 300 mg/kg-day dose levels. Additionally, putative target organs of nitrobenzene toxicity, such as liver, spleen, kidney, lung, brain, bone marrow, testis, epididymis, and uterus, were examined from rats and mice exposed at intermediate dose levels. There was no apparent autolysis among animals that were found dead (all in the 150 mg/kg-day dose group); tissues from these animals were also examined microscopically. Nine male and three female rats at the 150 mg/kg-day dose level died prior to study completion. The earliest deaths in the 150 mg/kg-day dose male and female rats were at day 67 (week 10) and day 38 (week 6), respectively. In the same group, six males also died on day 73 (week 11) and two more died on day 88 (week 13), while another female rat died on each of days 45 (week 7) and 60 (week 9). Clinical signs of toxicity, such as ataxia, head tilt, lethargy, and trembling, were evident, mostly in animals receiving 150 mg/kg-day and, to a lesser extent, 75 mg/kg-day. Overall, there was little change in body weight gain between control and treated groups, and the final body weights were not significantly different from controls at any dose level. In fact, the only sign of treatment-related body weight reduction was in the single surviving male rat receiving 150 mg/kg nitrobenzene. Organ weights appeared to have been dose dependently affected by nitrobenzene exposure, most notably in the case of liver, kidney, and testis (males). As shown in Tables 4-3 and 4-4, liver weights and their ratios to body weight were dose dependently increased over control levels and achieved statistical significance compared with controls at all dose levels. There were statistically significant changes in some hematologic parameters in rats exposed to nitrobenzene via gavage. In males, these changes achieved statistical significance compared with controls at a dose of 9. In females, the changes achieved statistical significance compared with controls at 37. Hematologic parameters, reticulocytes, and metHb levels in male F344 rats exposed to nitrobenzene via gavage for 90 days Dose (mg/kg-day) 0 9. Hematologic parameters, reticulocytes, and metHb levels in female F344 rats exposed to nitrobenzene via gavage for 90 days Dose (mg/kg-day) 0 9. Males at this dose level had enlarged livers, and those receiving 75 mg/kg-day and 150 mg/kg-day showed signs of testicular atrophy. The incidence of these and other histopathologic lesions in relation to dose is shown in Tables 4-7 and 4-8. Tables 4-7 and 4-8 also report the incidence of splenic congestion of grade 2 or higher. Selected histopathology findings in male F344 rats exposed to nitrobenzene for 90 days via gavage Tissue examined Spleen Congestion Congestion grade 2 Lymphoid depletion Liver Congestion Testis Atrophy Hypospermatogenesis Multinucleate giant cells Brain stem Hemorrhage Vacuolization Degeneration Malacia a 0 1/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 7/10 0/10 0/10 9. Sustained congestion causes the spleen to become more firm, enlarged, and fibrotic and renders the organ susceptible to trauma. Selected histopathology findings in female F344 rats exposed to nitrobenzene for 90 days via gavage Tissue examined Spleen Congestion Congestion grade 2 Lymphoid depletion Kidney Pigmentation Brain stem Hemorrhage Vacuolization Degeneration Malacia a 0 2/10 0/10 0/10 0/10 4/10 6/10 0/10 0/10 9.

For more information on laboratory changes with amoxicillin or clarithromycin, refer to their package inserts, Adverse Reactions section muscle relaxant baclofen purchase voveran 50 mg mastercard. Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and may result in a loss of therapeutic effect and the development of drug resistance muscle relaxant rocuronium discount voveran 50mg without prescription. Co-administration of saquinavir with proton pump inhibitors is expected to increase saquinavir concentrations, which may increase toxicity and require dose reduction muscle relaxant intravenous generic voveran 50mg free shipping. The clinical importance and the mechanisms behind these interactions are not always known spasms stomach pain buy cheap voveran 50mg on-line. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug infantile spasms 6 months old voveran 50mg visa. Reduced concentrations of atazanavir and nelfinavir For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole skeletal muscle relaxant quizlet 50mg voveran for sale. Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended. Dose reduction of saquinavir should be considered from the safety perspective for individual patients. There are also some antiretroviral drugs of which unchanged serum levels have been reported when given with omeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects). Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin, or amoxicillin. However, post-marketing reports of changes in prothrombin measures have been received among patients on concomitant warfarin and esomeprazole therapy. Concomitant use of esomeprazole 40 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Co-administration of cilostazol with esomeprazole is expected to increase concentrations of cilostazol and its above mentioned active metabolite. Therefore a dose reduction of cilostazol from 100 mg twice daily to 50 mg twice daily should be considered. Omeprazole, of which esomeprazole is an enantiomer, has been reported to interact with St. Tacrolimus Concomitant administration of esomeprazole and tacrolimus may increase the serum levels of tacrolimus. Combination Therapy with Clarithromycin Co-administration of esomeprazole, clarithromycin, and amoxicillin has resulted in increases in the plasma levels of esomeprazole and 14-hydroxyclarithromycin [see Clinical Pharmacology (12. Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions [see Warnings and Precautions in prescribing information for clarithromycin]. Because of these drug interactions, clarithromycin is contraindicated for co-administration with certain drugs [see Contraindications in prescribing information for clarithromycin]. Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use. Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole magnesium in rats and rabbits with doses about 68 times and 42 times, respectively, an oral human dose of 40 mg (based on a body surface area basis for a 60 kg person). However, changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 34 times an oral human dose of 40 mg (see Animal Data). Four epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H 2 -receptor antagonists or other controls. The number of infants exposed in utero to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population. A population-based retrospective cohort study covering all live births in Denmark from 19962009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837, 317 live births whose mothers did not use any proton pump inhibitor. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2. A retrospective cohort study reported on 689 pregnant women exposed to either H 2 -blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H 2 -blocker, or were unexposed was 3. A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% first trimester exposures). The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non-teratogens, and 2. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups. Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia. Animal Data Reproduction studies have been performed with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 41 times an oral human dose of 40 mg on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole magnesium. A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3. Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg/kg/day (about 17 times an oral human dose of 40 mg on a body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses equal to or greater than 14 mg/kg/day (about 3. Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis). Effects on maternal bone were observed in pregnant and lactating rats in a pre- and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg/kg/day (about 3. When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis). A pre- and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above. Esomeprazole is the S-isomer of omeprazole and limited data indicate that maternal doses of omeprazole 20 mg daily produce low levels in human milk. Twenty of 98 enrolled patients underwent endoscopy, and 6 patients were found to have erosive esophagitis on endoscopy at baseline. Efficacy was assessed by observing the time from randomization to study discontinuation due to symptom worsening during the fourweek, treatment-withdrawal phase. Juvenile Animal Data In a juvenile rat toxicity study, esomeprazole was administered with both magnesium and strontium salts at oral doses about 34 to 68 times a daily human dose of 40 mg based on body surface area. Increases in death were seen at the high dose, and at all doses of esomeprazole, there were decreases in body weight, body weight gain, femur weight and femur length, and decreases in overall growth [see Nonclinical Toxicology (13. No overall differences in safety and efficacy were observed between the elderly and younger individuals, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The major signs of acute toxicity were reduced motor activity, changes in respiratory frequency, tremor, ataxia, and intermittent clonic convulsions. Since esomeprazole is extensively protein bound, it is not expected to be removed by dialysis. As with the management of any overdose, the possibility of multiple drug ingestion should be considered. For current information on treatment of any drug overdose contact a Poison Control Center at 1-800-222-1222. Esomeprazole is the S-isomer of omeprazole, which is a mixture of the S- and R- isomers. Its molecular formula is (C 17 H 18 N 3 O 3 S) 2 Mg x 3 H 2 O with molecular weight of 767. The stability of esomeprazole magnesium is a function of pH; it rapidly degrades in acidic media, but it has acceptable stability under alkaline conditions. Each delayed-release capsule contains 20 mg, or 40 mg of esomeprazole (present as 22. The inactive granules are composed of the following ingredients: dextrose, xanthan gum, crospovidone, citric acid, iron oxide, and hydroxypropyl cellulose. The esomeprazole granules and inactive granules are constituted with water to form a suspension and are given by oral, nasogastric, or gastric administration. The S- and R-isomers of omeprazole are protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. By acting specifically on the proton pump, esomeprazole blocks the final step in acid production, thus reducing gastric acidity. This effect is dose-related up to a daily dose of 20 to 40 mg and leads to inhibition of gastric acid secretion. This increase reached a plateau within two to three months of therapy and returned to baseline levels within four weeks after discontinuation of therapy. Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop esomeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H 2 -receptor antagonists. Human gastric biopsy specimens have been obtained from more than 3,000 patients (both children and adults) treated with omeprazole in long-term clinical trials. Omeprazole given in oral doses of 30 or 40 mg for 2 to 4 weeks had no effect on carbohydrate metabolism, circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin, or secretin. Bioequivalency is based on a single dose (40 mg) study in 94 healthy male and female volunteers under fasting condition. At repeated once-daily dosing with 40 mg, the systemic bioavailability is approximately 90% compared to 64% after a single dose of 40 mg. The apparent volume of distribution at steady state in healthy volunteers is approximately 16 L. Following administration of equimolar doses, the S- and R-isomers are metabolized differently by the liver, resulting in higher plasma levels of the S- than of the R-isomer. Excretion the plasma elimination half-life of esomeprazole is approximately 1 to 1. Approximately 80% of an oral dose of esomeprazole is excreted as inactive metabolites in the urine, and the remainder is found as inactive metabolites in the feces. Pharmacokinetics: Combination Therapy with Antimicrobials Esomeprazole magnesium 40 mg once daily was given in combination with clarithromycin 500 mg twice daily and amoxicillin 1000 mg twice daily for 7 days to 17 healthy male and female subjects. The observed increase in esomeprazole exposure during coadministration with clarithromycin and amoxicillin is not expected to produce significant safety concerns. The pharmacokinetic parameters for clarithromycin and amoxicillin were similar during triple combination therapy and administration of each drug alone. This increase in exposure to 14-hydroxyclarithromycin is not considered to be clinically significant. Concomitant Use with Clopidogrel Results from a crossover study in healthy subjects have shown a pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation was related to the change in the exposure to clopidogrel active metabolite. The total exposure for the 10 mg dose in patients aged 1 to 5 years was approximately 30% higher than the 10 mg dose in patients aged 6 to 11 years. The total exposure for the 20 mg dose in patients aged 6 to 11 years was higher than that observed with the 20 mg dose in 12 to 17 year-olds and adults, but lower than that observed with the 40 mg dose in 12 to 17 year-olds and adults. No dosage adjustment is recommended for patients with mild to moderate hepatic insufficiency (Child Pugh Classes A and B). However, in patients with severe hepatic insufficiency (Child Pugh Class C) a dose of 20 mg once daily should not be exceeded [see Dosage and Administration (2)]. Other pharmacokinetic observations Co-administration of oral contraceptives, diazepam, phenytoin, or quinidine did not seem to change the pharmacokinetic profile of esomeprazole. Clarithromycin Susceptibility Test Results and Clinical/Bacteriologic Outcomes: the baseline H. Susceptibility Test for Helicobacter pylori: For susceptibility testing information about Helicobacter pylori, see Microbiology section in prescribing information for clarithromycin and amoxicillin. Effects on Gastrointestinal Microbial Ecology: Decreased gastric acidity due to any means, including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and possibly Clostridium difficile in hospitalized patients. In two 24-month oral carcinogenicity studies in rats, omeprazole at daily doses of 1. By the second year the difference between treated and control rats was much smaller (46% vs. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. Esomeprazole was negative in the Ames mutation test, in the in vivo rat bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test.

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