By U. Basir. Olivet College.

Lavage is useful in cases in which the hydrocarbon has an inherent systemic toxicity or contains additives with known toxicity buy cheap indinavir 400mg on line. Activated charcoal is indicated only in cases of a suicide attempt or in cases in which another adsorbable toxic substance have been co-ingested order line indinavir. Exposure Organophosphates are very efficiently absorbed from the skin and mucous membranes purchase generic indinavir on line. The majority of organophosphate poisoning occurs by accidental or occupational exposure, but poisoning may also be due to suicide attempts, homicide attempts, or chemical warfare. In a child less than one year of age with an organophosphate poisoning, child abuse or neglect may be suspected. In anyone older than 6 years of age, a suicide attempt should be considered in the differential. Healthcare workers must be very cautious to prevent self-contamination when caring for an exposed patient. When caring for a patient with organophosphate poisoning, it is important to remember than any vomited material should be treated as a chemical spill. The bronchorrhea can be significant with frothy and/or bloody sputum and severe pulmonary edema. Cardiac depression and cardiovascular collapse may occur, and toxic cardiomyopathy may be present in severe poisonings. Miscellaneous effects to be aware of include pancreatitis, hyperglycemia, hypothermia, and a characteristic garlic odor that may aid in diagnosis when an unknown toxin has been ingested. When cholinesterase activity is 10-20% of baseline, the patient will likely experience generalized weakness, difficulty speaking, fasciculations, and miosis; this is moderate poisoning. In severe poisoning the cholinesterase level is generally less than 10% of baseline; these patients are likely to have the most severe symptoms as described above. Treating personnel should take care to avoid contact with contaminated skin, clothing, or body fluids. The patient should be well oxygenated before treatment of symptoms, as administration of atropine may precipitate ventricular dysrhythmias in a patient that has poor tissue oxygenation. Decontamination: All clothing should be removed and bagged as hazardous materials. It is during this skin decontamination that healthcare workers are in the most danger of exposure. Tachycardia and dilated pupils are not contraindications for atropine administration when given for an acute organophosphate poisoning. The end point of treatment should be determined by symptom resolution with concomitant lab testing for cholinesterase activity fat-soluble organophosphates may have a prolonged release and potential to cause recurrent symptoms after therapy has been discontinued. When present, these effects may include dizziness, blurry vision, and diastolic hypertension. In the case of hypotension that is not relieved by administration of atropine, trendelenburg, fluid resuscitation with normal saline, and vasopressors as indicated by monitoring of central venous pressure might become necessary. Benzodiazepines are first line for seizures; however, if seizures continue another anticonvulsant such as phenobarbital may be added. It is available in various formulations, including liquid, tablet, capsule, and suppository. It has an excellent safety profile in therapeutic doses, but hepatotoxicity can develop with overdoses. The liver metabolizes more than 90% of acetaminophen to glucuronide and sulfate conjugates, which are eliminated in the urine. In children, sulfation is the primary pathway until age 10-12 years; glucuronidation predominates in adolescents and adults. The maximum daily dose of acetaminophen is 4 g in adults and 90 mg/ kg in children. Clinical Presentation • In acute exposures, mortality and morbidity are decreased in pediatric patients compared to mortality and morbidity in adults. Nomogram tracking begins at 4 hours postingestion and ends at 24 hours postingestion. The upper line is the probable line, and 60% of patients with plots above this line develop hepatotoxicity. In severe overdose, transaminase elevation can develop as early as 12-16 hours after ingestion. Care • Gastric lavage – A recent position statement recommends that gastric lavage should not be routine for gastric decontamination, but should be limited to patients with recent (within 60 min) and potentially life-threatening toxicity. In addition, large amounts of ingested iron overwhelm normal gastrointestinal barriers, resulting in massive iron absorption. Iron also causes massive post-arteriolar dilatation, increased capillary permeability and coagulopathy leading to severe acidosis and shock, within first few hours. Iron affects almost every organ in the body being a systemic intra-cellular poison. Up to 12 hr Apparent stabilization Symptoms subside 12-48 hr Mitochondrial toxicity Shock, acidosis, coma, seizures, hyperglycemia, Coagulopathy, acute tubular necrosis, hypoglycemia. Dose of Ingested Iron Assessment could be based on the elemental iron content of the specific product as well as its formulation. Hence, a child should be assumed to have consumed the higher value of possible ingested dose. A triage has been suggested based on amount of alleged iron ingestion < 20 mg/Kg - Little risk for toxicity. These may be useful indicators of severe toxicity, and help in therapeutic decision- making. If child remains asymptomatic for 6 to 8 hours after ingestion, further intervention is usually not required. Some recommend a desferrioxamine (40- 50 mg/Kg, maximum 1 g) challenge test immediately at admission to detect toxic potential while decontamination is being performed. However, a change of urine color to vinrose is not a consistent finding even if serum iron is >350 µg/dl and it may lead to a delay of 1 to 3 hours. Decontamination Gastric lavage with the largest available tube should be done at the first-contact health care facility if a child has ingested iron in excess of 20 mg/Kg or is symptomatic. A post lavage abdominal radiograph should be obtained to look whether lavage has cleared all the tablets from stomach; if not, lavage should be repeated. Tap water or normal saline is the best lavage solution; bicarbonate, phosphate, magnesium hydroxide or desferrioxamine do not have any proven advantage. It will cause diarrhea within 20 minutes and clear effluent will be apparent in as early as 90 minute Peglec® is safe for children and does not cause fluid and electrolyte changes. Alternatively, nasogastric infusion of normal saline (30-40 ml/hr) for 2-3 hours may be used.

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The mean seizure frequencies during the 8-week approximately 1 year afer initiation of felbamate order generic indinavir from india, and to 1 buy indinavir 400mg on-line. Initial analysis sy syndromes discount 400 mg indinavir with mastercard, a decrease in seizure frequency of 50% or more was showed no signifcant diference in seizure frequency between pla- seen in 63% afer treatment with felbamate was initiated [67]. Patients Adverse effects were hospitalized for 8 days for observation and, if they remained in In animal models, felbamate showed little toxicity [69]. Studies of the study, they were discharged and followed as outpatients for an carcinogenicity afer high doses demonstrated a statistically sig- additional 21 days. In the felbamate group, 54% made it to the end nifcant increase in hepatic cell adenomas in some rodents, and of the observation period without a fourth seizure, whereas only an increase in benign interstitial cell tumours of the testes in male 12% of the placebo group made it to this end-point (Kaplan–Meier rats [68]. In the same study, during the presurgi- or teratology studies in rats and rabbits [68]. The most common adverse efects in polytherapy studies to demonstrate the efectiveness of felbamate in intractable trials were anorexia, vomiting, insomnia, nausea, dizziness, som- patients. In data provided by Carter Wallace, were not intended to be used as models of monotherapy. In one post-marketing use study, felbamate haematological toxicity, retention rate on felbamate in a clinical set- was initiated in 132 persons with chronic refractory epilepsy afer ting was favourable, as it was in a post-marketing study in which its release. Tree or more months afer initiation, felbamate had 91 of 132 refractory patients had enough clinical efcacy and lack been discontinued in 24 patients because of adverse efects. Gas- of side-efects to warrant continuance of felbamate for 3 months or trointestinal symptoms were the most common single reason given, more afer initiation [63]. However, as felbamate came into wider use, reports of serious ad- verse events surfaced. Trombocytopenia was described in one re- reports indicates that 78% were female, 50% were aged 17 years port [72]. In addition, 11 cases of hepa- seven, the incidence of hepatic failure would be estimated at 64 per titis with four deaths had been reported. As of May 1995, Carter Wal- million, or a risk estimate for hepatic failure of 1 per 18 500–25 000 lace had evidence of 31 domestic post-marketing reports of aplastic exposures. Statistics regarding valproic acid reported hepatic-relat- anaemia and 14 cases of hepatitis with eight deaths (Table 35. Of population, and 1 in 500–800 cases in high-risk young children un- the cases reported, 23 (74%) met all of the criteria of the Interna- der the age of 2 years receiving valproic acid polypharmacy [77]. Felbamate Tese data suggest that the hepatotoxicity associated with felbamate was judged to be the only cause in three cases, and the most likely is in the general range seen with valproic acid [75]. Using a denominator of 110 000 age range difers markedly, with felbamate safer in the paediatric persons exposed, the ‘most probable’ incidence was calculated to be population but worse in adults, with just the opposite for valproic 127 per million (lower limit, 27; upper limit, 209), with the general acid. For both felbamate-induced aplastic anaemia and hepatotox- population rate for aplastic anaemia being 2 per million [74]. Patient history and demographics suggest several features that Felbamate is excreted in the urine and one case of urolithiasis may identify the high-risk patient. Toxic epidermal necrolysis afer initiation of fel- developed aplastic anaemia revealed that an underlying immuno- bamate has also been reported [80]. Only one paediatric pa- 15 years, a relative paucity of information exists about its clinical tient (aged 18 years) was diagnosed with aplastic anaemia, and she use. The most up-to-date review on the felbamate literature is de- had a prior diagnosis of systemic lupus erythematosus [75]. New exposures to felbamate are estimated at between 3200 apy prior to aplastic anaemia ranged from 23 to 339 days (mean 173 and 4200 patients annually; over the past 10 years, approximate- days) [75]. No cases reported up to the time of the review occurred ly 35 000 patients have been started on felbamate. Since 1994, one in persons treated for more than 1 year, although in one additional case of aplastic anaemia has been reported, which was described in case subsequently reported, the patient had been on felbamate for 2000 in a 42-year-old woman who had been taking felbamate for 8 years [76]. One case of throm- A total of 18 cases of hepatic failure were reported in patients bocytopenia in a 14-year-old girl was reported in 2007. Evaluation of these was discontinued, thrombocytopenia resolved completely, but Felbamate 477 4 months later aplastic anaemia occurred, thought to be unrelat- and reduced further as symptoms and blood levels indicate. Two cases of liver failure (one in 1995 and one in be expected that doses for children may be larger than those for 1996) have been reported in felbamate patients since 1994; one was adults, and in our experience we have used doses of up to 80 mg/kg. A prospective database afliated with an epilepsy centre identifed 77 long-term users of felbamate (data Laboratory and clinical monitoring collected between 1986 and 2006) [36]. The study therapy and for a signifcant period of time afer discontinuation of demonstrated signifcant weight loss in the frst year of felbamate felbamate. Liver function tests are recommended every 1–2 weeks use, but weight loss was not sustained over long-term use. It is not at all certain, however, that routine cant reductions were noted in generalized tonic–clonic seizures and monitoring of haematological and hepatic parameters will be efec- simple partial seizures. More important than laboratory testing tory parameters pertinent to liver or bone marrow function were is a careful review of the medical history and the avoidance of use seen; these results support the concept that the most serious fel- of felbamate in patients who have a high-risk profle. Patients considered unsuitable candidates for fel- and symptoms include severe lethargy, nausea and vomiting, fu- bamate include patients with new-onset epilepsy and patients with like symptoms, easy bruising and unusual bleeding. A similar conclusion was reached in 1999 by a joint American Academy of Neurology and American Epilepsy Society practice advisory [68]. Comparative anticonvulsant activity and In adults, felbamate can be initiated at 1200 mg/day in three or four neurotoxicity of felbamate and four prototype antiepileptic drugs in mice and rats. A neuropharmacological evaluation of In inpatient settings, felbamate can be titrated over a few days, es- felbamate as a novel anticonvulsant. Simultaneous assay of felbamate plus carba- mazepine, phenytoin, and their metabolites by liquid chromatography with mo- reduced [55]. Determination of the anticon- by further reductions as felbamate dose is increased. Determination of the anti- especially if the goal is to attain monotherapy with felbamate. Some convulsant felbamate and its three metabolites in brain and heart tissue of rats. J patients have tolerated doses as high as 7200 mg/day as monother- Chromatogtr 1993; 614: 285–292. Efects of anticonvulsant drugs on ing patients is to start at approximately 20 mg/kg and increase to 4-aminopyridine-induced seizures in mice. Efects of felbamate and other anticon- vulsant drugs in two models of status epilepticus in the rat. Interaction of felbamate with several other antiepileptic drugs against seizures induced by maximal electroshock in mice. Interaction of felbamate and diazepam permit patients to have an adequate exposure to this drug. Pharmacol tient with refractory epilepsy with particularly intense seizures or a Biochem Behav 1991; 40: 109–113. Mechanism of action of the anticonvulsant day with weekly incremental increases to 45 mg/kg/day. A review of its pharmacodynamic and phar- concentrations afer felbamate initiation [Abstract].

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Linear determinants of six amino acids interact with Antigens and Immunogens 169 specifc antibody order indinavir toronto. Occasionally discount indinavir 400mg online, linear determinants may be on the surface of a native folded protein purchase indinavir 400 mg free shipping, but they are more commonly unavailable in the native confguration and only become available for interaction with antibody upon denatur- ation of the protein. A linear epitope is an antigenic determinant of a protein mole- cule recognized by an antibody that consists of a linear sequence of amino acids within the protein’s primary structure. An oligosaccharide determinant is an epitope or antigenic determinant of a polysaccharide hapten that consists of rela- tively few, i. A sequential determinant is an epitope whose specifcity is determined by the sequence of several residues within the antigenic determinant rather than by the molecular confgu- ration of the antigen molecule. A peptide segment of approx- imately six amino acid residues represents the sequential determinant structure. Nonsequential epitopes are antigenic determinants that are widely separated in the primary sequence of the polypeptide chain but are near one another in the tertiary structure of the molecule. This is a consequence of the formation of intramolecular hydrogen bonds joining carbonyl oxygen Quaternary structure (Figure 3. Two or more folded poly- the local spatial organization of polypeptide chain segments peptide chains packed into a confguration such as a tetramer. Denaturation is changing a protein’s secondary and tertiary structure (coiling and folding) to produce a confguration that Heme group figure 3. Whereas storage causes slow denaturation, heating or chemical treatment may A trinitrophenyl (picryl) group (Figure 3. Only if complexed to a carrier molecule prior to administration can a hapten induce an immune response. The conjugation of a hapten to a carrier macromolecule can enable it to induce a hapten-specifc B and T cell response. O (Hapten + Carrier) the carrier protein supplies T cell epitopes that are requisite Tyrosine-containing protein (carrier) for B cell–T cell cooperation. Carrier effect: To achieve a secondary immune response to a hapten, both the hapten and the carrier used in the initial immunization must be employed. The cells producing the antibodies are tein carrier with a hapten, or it may refer to the labeling of a derived from B cells. The experimental design for demonstrating the carrier effect involves adoptive Carrier specifcity refers to an immune response, either transfer of hapten-sensitive B cells and of T cells primed with humoral antibody or cell-mediated immunity, that is specifc one or another carrier. The primed cells are those which have for the carrier portion of a hapten–carrier complex that has already had a past opportunity to encounter the antigen. The carrier-specifc part of the immune response does not react with the hapten either by Dinitrofuorobenzene (2,4-dinitro-1-fuorobenzene) itself or conjugated to a different carrier. When placed on the macromolecules that serve as carriers for simple chemical skin, it leads to contact hypersensitivity. The immunization of rabbits or other animals with a hapten–carrier complex leads to the the hapten inhibition test is an assay for serological char- formation of antibodies specifc for the hapten as well as the acterization or elucidation of the molecular structure of an carrier. T cells were later shown to be carrier specifc and epitope by blocking the antigen-binding site of an antibody B cells hapten specifc. Aromatic amine derivatives can be coupled to side chains of selected amino acid residues to prepare A hybrid hapten is a hydrophobic type of hapten that lies protein–hapten conjugates, which, when used to immunize within the folds of a protein carrier away from the aqueous experimental animals such as rabbits, stimulate the synthe- solvent, creating a new spatial structure. The diazonium salt is then combined with the protein at response of a host to the individual components of a vaccine a pH that is slightly alkaline. The reaction products include might be less than if they had been injected individually. Antigen unmasking the exposure of tissue antigens using an antigen unmasking solution based on a citric acid formula, A diazo salt is a diazonium salt prepared by diazotization is highly effective at revealing antigens in formalin-fxed, from an arylamine to yield a product with a diazo group. Doctrine of original antigenic sin: the immune response An azoprotein is produced by joining a substance to a pro- against a virus to which an individual was previously tein through a diazo linkage –N = N–. Karl Landsteiner (in exposed, such as a parental strain, may be greater than it is early 1900s) made extensive use of diazotization to prepare against the immunizing agent, such as type A infuenza virus hapten–protein conjugates to defne immunochemical speci- variant. An antigen binding site is the location on an antibody mol- Original antigenic sin is when an individual is exposed to an ecule where an antigenic determinant or epitope combines antigen that is similar but not identical to an antigen to which with it. The antigen-binding site is located in a cleft bordered he was previously exposed by either infection or immuniza- by the N-terminal variable regions of heavy and light chain tion, and the immune response to the second exposure is still parts of the Fab region. This was frst noticed in important immunologic functions by virtue of its mass of the infuenza virus infection. Due to antigenic drift and anti- Kupffer cells, which represent the major part (90%) of the genic shift in infuenza virus, reinfection with an antigeni- body’s phagocytic capacity. Antigens escaping the intestinal cally altered strain generates a secondary immune response barrier by passage through the liver are removed through a that is specifc for the infuenza virus strain that produced an process called antigen clearance. Other highly immunogenic epitopes on sec- position at the border between the splanchnic and systemic ond and subsequent viruses are ignored. In this phenomenon, circulations substantiates its function as a flter for noxious B cell clones activated by an original antigen are reactivated substances, whether antigen or otherwise. The same removal in response to a new cross-reactive antigen, which possesses mechanism is operative during liver passage in situations in novel B cell epitopes in addition to T cell epitopes present on which antigen circulates in the blood. Induced ft is the theory that an antigen may affect confor- Antigenic variation represents a mechanism whereby mation of the antigen-binding site of an antibody molecule selected viruses, bacteria, and animal parasites may evade or of a T cell receptor to render a better ft with antigen. The variability among infectious disease agents is of critical signifcance in the development Antigen clearance: Exogenous clearance is a principal of effective vaccines. Antigen removal is by phagocy- antigens of the viruses, bacteria, or animal parasite in which tosis, cytolysis, or complement-mediated elimination. By the time the host has developed a protective Antigens and Immunogens 173 figure 3. The appearance of a new type A infuenza virus signals the addition of a new epitope, even though several original antigenic determinants are still pres- ent. In contrast to antigenic drift, antigenic shift involves a principal alteration in a genome attributable to gene rear- rangement between two related microorganisms. Since anti- genic shift involves the acquisition of totally new antigens against which the host population is not immune, this altera- figure 3. It is the result of genetic ganisms by new antigens to which the host is not immune, transformation between gonococcal strains. This is also thereby permitting survival of the microorganism or animal observed in penicillin resistance of several bacterial species parasite and its evasion of the host immune response. Antigenic variants repre- immunogen that can stimulate B cells to synthesize antibod- sent those viruses that have survived exposure to the host’s ies without participation by T cells. The progeny virions generated possess new combinations of genome segments and, there- fore, new proteins. It refers to a major antigenic change in which a strain with distinctive new antigens may appear, such as Asian or A2 infuenza in 1957. Infuenza virus antigenic shift is attributable mainly to alterations in the hemagglutinin antigens with less frequent alterations in figure 3. Heterophile antigens induce the formation of hetero- saccharides, glycolipids, and nucleic acids. When T lympho- phile antibodies when introduced into a species where they cytes and macrophages are depleted, no antibody response are absent.

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