By V. Gorn. Antioch University Yellow Springs OH.
These radionuclides are allowed to decay in storage and monitored before disposal buy discount carbamazepine 200 mg online muscle relaxant pakistan. If the radioactivity of the waste cannot be distinguished from back- ground carbamazepine 400mg without prescription spasms during pregnancy, it can be disposed of in the normal trash after removal or defacing of all radiation labels buy 400 mg carbamazepine overnight delivery spasms icd 9 code. This method is most appropriate for 99m 123 201 111 67 131 shortlived radionuclides such as Tc discount 400 mg carbamazepine spasms that cause coughing, I, Tl, In, Ga and I. Radioac- tivities should be stored separately according to half-lives for convenience of timely disposal of each radionuclide. Excreta from humans undergoing medical diagnosis or treatment with radioactive material are exempted from these limitations. To adopt this method of radioactive disposal, one must determine the total volume and the ﬂow of sewer water in the institution and the number of users of a speciﬁc radionu- clide so that for each individual user, a limit can be set for sewer disposal of the radionuclide in question. Transfer to Authorized Recipient This method of transfer to an authorized recipient is adopted for longlived radionuclides and usually involves transfer of radioactive wastes to autho- rized commercial ﬁrms that bury or incinerate at approved sites or facilities. Although the columns of the 99Mo–99mTc generators may be decayed to background for disposal to normal trash, a convenient method of disposing of this generator is to return them to the vendors, who let them decay and later dispose of them. Normally, the used generator is picked up by the authorized carrier when a new one is delivered. Radiation Regulations and Protection Other Disposal Methods A licensee may adopt methods of radioactive waste disposal different from those mentioned here, provided regulatory agency approval is obtained. Impact of such disposal methods on environment, nearby facilities, and population is heavily weighed before approval. Incineration of solid radio- active waste and carcasses of research animals containing radioactive 133 materials is allowed by this method. Records must be maintained as to the date of storage and the amount and kind of activity stored in a waste disposal log book. The date of disposal and the amount of disposed activity must also be recorded in the log book, along with the initials of the individual disposing of the waste. Radioactive Spill Accidental spillage of radioactivity can cause unnecessary radiation exposure to personnel and must be treated cautiously and expeditiously. A major spill usually occurs when the spilled activity cannot be contained in a normal way and can cause undue exposure to personnel. Areas, personnel, and equipment must be decontami- nated, keeping in mind the principle of containment of radioactivity. Recordkeeping Records must be maintained for the receipt, storage, and disposal of radioactive materials, as well as for various activities performed in the radi- ation laboratories. The 99m 99 99m Tc activity is eluted from the Mo- Tc generator and reagent kits are 99m used to prepare Tc-labeled radiopharmaceuticals according to instruc- tions given by the manufacturer in the package inserts. Applications, Amendments, and Notiﬁcations As already mentioned, applications for a license and its renewals must be made by the licensee’s management for the medical uses of by-product materials. Amendments to the license must be made by the licensee’s man- agement for the following: (a) Appointment or discontinuation of an authorized user, radiation safety ofﬁcer, authorized medical physicist, or authorized nuclear pharmacist (b) Change of name or address of the licensee (c) Change or addition of the use areas (d) Use of excess or new by-product materials not permitted before in the license 284 16. Radiation Regulations and Protection Notiﬁcation of the above must be made within 30 days of occurrence. Licenses with Type A speciﬁc license of broad scope are exempt from these requirements. There is no requirement for periodic review of the supervised individual’s work and records. The licensee is responsible for the acts and omissions of the supervised individuals. The written directive must be dated and signed by an authorized user and must contain the patient’s name, the dosage, the name of the drug, and route of administration. A revision of the written directive can be made, if necessary, provided it is signed and dated by the authorized user before administration. In case of an emergency, an oral revision to an existing written directive is acceptable, which must be followed by a written directive within 48 hours. The identity of the patient may be veriﬁed by the name, driver’s license, birthday, any hospital’s I. For unit dosages, the activity can be determined by direct measurement or by the decay correction of the activity provided by the licensed manu- facturer. Radiation Regulations and Protection mined by direct measurement, a combination of measurement of radioac- tivity and mathematical calculations, or a combination of volumetric mea- surements and mathematical calculations based on the activity provided by the manufacturer. Unless otherwise directed by the authorized user, the licensee may not use a dosage if it does not fall within the prescribed dosage range, or if it differs from the prescribed dosage by more than 20%. The licensees who use only unit dosages supplied by the manufacturer may not need to have a dose calibrator. Each syringe or vial shield also must Medical Uses of Radioactive Materials 287 be labeled, unless the label on the syringe or vial is visible through the shield. The survey must be performed at the end of each day of use with a radiation detection instrument. Calibration must be made in all scales with readings up to 1000mrem (10mSv) per hour with a radiation source, and two separated readings must be calibrated on each scale or decade (digital) that is used to show compliance. The licensee may not use the survey instruments if the difference between the indicated expo- sure rate and the calculated exposure rate is more than 20%. Training and Experience Requirements for Medical Uses of By-Product Materials Authorized users, radiation safety ofﬁcers, and nuclear pharmacists are required to have appropriate training and experience for medical uses of by-product materials. Normally there are two methods of approval: (1) cer- tiﬁcation by a speciﬁc medical specialty board, and (2) training and work experience in radionuclide handling techniques applicable to speciﬁc medical use of by-product material. The training part includes a speciﬁed period of didactic classroom and laboratory training in the areas of (a) radiation physics and instrumenta- 288 16. Radiation Regulations and Protection tion, (b) radiation protection, (c) mathematics pertinent to radioactivity, (d) chemistry of by-product material, and (e) radiation biology and radiation dosimetry (for radiation safety ofﬁcer). The work experience must be under an authorized user, radiation safety ofﬁcer, or nuclear pharmacist depending on the speciﬁc authorization of by- product material requested and must include (a) ordering, receiving, and unpacking radioactive materials, and surveying; (b) calibration of dose calibrators and survey meters; (c) calculating, measuring, and preparing dosages for patients; (d) procedures for spill management; (e) safely admin- istering dosages to patients (for authorized users only); and (f) elution of radioactive generators (for localization and imaging studies). In addition, approval by the training and experience method requires a written certiﬁcation by a preceptor that the individual has acquired com- petence in the techniques to function independently for a speciﬁed use of by-product material. The required hours of training and experience vary for different types of uses of radioactive material and are listed below. A medical event Medical Uses of Radioactive Materials 289 occurs when a dose exceeds 5rem (0. The report must include the licensee’s name, prescribing physician’s name, brief description of the event, cause of the event, effect of the event, if any, on the individual, corrective action taken, if any, and whether the affected individual or his or her relative or guardian has been notiﬁed. The individual’s name or identiﬁcation number shall not be included in the report. The licensee shall notify the individual and the referring physician of the event no later than 24 hours after the discovery, unless the referring physi- cian personally takes the responsibility of informing or not informing the individual based on medical judgment. If a verbal notiﬁcation is made, the licensee shall inform the individual of the availability of a written descrip- tion of the event, which the licensee will provide upon request. Radiation Regulations and Protection 5rem (50mSv) total effective dose equivalent, or has resulted in unintended permanent functional damage to an organ or biological system of the child. The conditions, timing, and descriptions of the report are identical to those of the medical events described above. Practically in nuclear medicine, patients treated with 131I-NaI are commonly considered under these regulations. The patient-speciﬁc calculations depend on the choice of the occupancy factor and the physical or effective half-life.
This is expected because the initial Pearson’s correlations showed a signiﬁcant association between length and head circumference with an r value of 0 carbamazepine 100mg sale spasms to right side of abdomen. As a result of the mutlicollinearity buy carbamazepine 100 mg cheap muscle relaxant food, the standard error for length has inﬂated from 0 buy carbamazepine 100mg otc muscle relaxer x. Head circumference is expected to vary with length as a result of common factors that inﬂuence body size and growth carbamazepine 100mg with mastercard muscle relaxant non drowsy. In this situation, head circumference should be classiﬁed as an alternative 230 Chapter 7 outcome rather than an independent explanatory variable because it is on the same developmental pathway as length. Each model building situation will be different but it is important that the relationships between the variables and the purpose of building the model are always carefully considered. If an interactive effect is present, the two lines would have different slopes and would cross over or intersect at some point. To test for the presence of an interaction, the two variables are multiplied to create a cross-product term, which is included in the multiple regression model. In the following equation, the fourth term represents an interaction between length and gender. Also, once again, coding of binary variables as 0 and 1 is helpful for interpreting interactions. When gender is coded as 1, the third term will add a ﬁxed amount to the prediction of the outcome variable and the fourth interactive term will add an amount that increases as length increases, thereby causing the regression lines for each gender to increasingly diverge. The regression equation for a model with an interaction term would be as follows: Weight = a +(b1 × Length)+(b2 × Gender)+(b3 × Length × Gender) It is preferable to explore evidence that an interaction is present rather than testing for all possible interactions in the model. Testing for all interactions will almost certainly generate some spurious but signiﬁcant P values. To avoid multicollinearity, the explanatory variables and their interaction can be centered before inclusion in the regression model,7 which will be discussed later in this chapter. The regression plots can then be inspected to assess whether there is a different linear relationship across the groups. When the values of the data points are a long way from zero, as in these plots, Correlation and regression 231 Gender: Male R2 Linear = 0. Correlation and regression 233 the y intercepts have no meaningful interpretation although they can indicate that the slopes are different. This similarity of slopes suggests that there is no impor- tant interaction between length and gender in predicting weight. The graphs can be repeated to investigate a possible interaction between head circumference and gender. If plotted on the same ﬁgure, the two regression lines would intersect at some point indicating an interaction between head circumference and gender. In practice, head circumference would be omitted from the model because of its collinearity with length but it is included in this model solely for demonstrating the effect of an interaction term. If an interaction term is included then both derivative variables, that is, head circumference and gender, must be retained in the model regardless of their statistical signiﬁcance. Once an interaction is present, the coefﬁcients for the derivative variables have no interpretation except that they form an integral part of the mathematical equation. The Coefﬁcients table shows that inclusion of the interaction term inﬂates the standard error for head circumference from 0. These standard errors have inﬂated as a result of the collinearity with the interaction term and, as a result, the tolerance value in the Excluded Variables table is very low and unacceptable at 0. In addition, while the change in R square from Model 1 to Model 2 was signiﬁcant, it is important to assess the clinical signiﬁcance of this increase, in conjunction with a less precise model. This example highlights the trade-off between building a stable predictive model and deriving an equation that describes an interaction between variables. Multicollinearity caused by interactions can be removed by centering12 which is described later in this chapter. Correlation and regression 235 The ﬁnal model with all variables and the interaction term included could be consid- ered to be over-ﬁtted. By including variables that explain little additional variation and by including the interaction term, the model not only becomes complex but the preci- sion around the estimates is sacriﬁced and the regression assumptions of independence are violated. Head circumference should be omitted because of its relation with length and because it explains only a small additional amount of variation in weight. Once the ﬁnal model is reached, the remaining regression assumptions should be conﬁrmed. The residual distances are converted to standardized residuals that are in units of standard deviations from the regression. Standardized residuals are assumed to have a normal or approximately normal distribution with a mean of zero and a standard deviation of 1. Given the characteristics of a normal distribution, it is expected that 5% of stan- dardized residuals will be outside the area that lies between −1. In addition, 1% of standardized residuals are expected to lie outside the area between −3and+3 standard deviations from the mean. As the sample size increases, there will be an increasing number of potential outliers. In this sample size of 550 babies, it is expected that ﬁve children will have a standardized residual that will be outside the area that lies between −3and+3 standard deviations from the mean. The residual for each case can be saved to a data column using the Save option and the plots of the residuals can be obtained while running the model as shown in Box 7. The normality of the residuals can then be inspected using Analyze → Descriptive Statistics → Explore as discussed in Chapter 2. The Casewise Diagnostics table shows the cases that are more than three standard deviations from the regression line. There is only one case that has a standardized residual that is more than three standard deviations from the regression, that is, the baby with a weight of 5. Regression Coefﬁcientsa Unstandardized Standardized Collinearity coefﬁcients coefﬁcients statistics Model B Std. This is the minimum and maximum distances of babies from the equation, which is the variation about the regression. The standardized predicted values and standardized residuals shown in the Residuals Statistics table are expressed in units of their standard deviation and have a mean of zero and a standard deviation of approximately or equal to 1, as expected when they are normally distributed. The variance around the residuals can also be used to test whether the model vio- lates the assumption of homoscedasticity, that is, equal variance over the length of the regression model. Univariate outliers should be identiﬁed before ﬁtting a model but multivariate outliers, if present, are identiﬁed once the model of best ﬁt is obtained. Outliers that cause a poor ﬁt degrade the predictive value of the regression model; however, this has to be balanced with loss of generalizability if the points are omitted. Multivariate outliers are data values that have an extreme value on a combination of explanatory variables and exert too much leverage and/or discrepancy (see Chapter 5). Data points with high leverage and low discrepancy have no effect on the regression line but tend to increase the R square value and reduce the standard errors. On the other hand, data points with low leverage and high discrepancy tend to inﬂuence the 238 Chapter 7 Histogram dependent variable: weight (kg) Mean = 1. Correlation and regression 239 Scatterplot dependent variable: weight (kg) 4 2 0 −2 −3 −2 − 1 2 3 Regression standardized predicted value Figure 7. Data points with both a high leverage and a high discrepancy inﬂuence the slope, the intercept and the R square value. Thus, a model that contains problematic data points with high leverage and/or high discrepancy values may not generalize well to the population.
Disorders associated with defects in solute transporters carbamazepine 100 mg discount muscle spasms yahoo answers, such as severe diarrhea in glucose/galactose malabsorption and pri- mary bile acid malabsorption may be associated with pronounced general changes in drug absorption cheap carbamazepine 100mg with mastercard muscle relaxant creams over the counter. Several investigations are aimed at clarifying the role of trans- porters in drug absorption buy cheap carbamazepine 200mg line spasms of the esophagus, disposition carbamazepine 100 mg muscle relaxant drugs methocarbamol, and targeting. Another important gene family is the biogenic amine transporters, which regu- late neurotransmitter levels in synaptic transmission, with a number of documented variants that may affect function. These transporters are the direct target receptors for numerous drugs, including antidepressants and cocaine. Allelic variations, in particular of the serotonin transporter, are associated with the modulation of com- plex behavior and may play a signiﬁcant role in therapy with speciﬁc serotonin transporter inhibitors. Variation in neurotransmitter receptors can also be the cause of treatment failure. Genetic polymorphism of the β2-adrenoreceptor can alter the process of signal transduction by these receptors. Polymorphisms in drug target genes that can inﬂuence drug response are listed in Table 4. Protein kinases are coded by more than 2,000 genes and thus constitute the largest single enzyme family in the human genome. Amplicon modeling, primer design and assay vali- dation have been established for over 1,600 amplicons within 92 different kinase genes. Kinase mutation mapping can be used to pinpoint responder populations and facilitate the development of person- alized medicine. Effect of Genetic Polymorphisms on Disease Response to Drugs Genetic polymorphism of genes and gene products may inﬂuence the disease- modifying effects of drugs. It offers 1,936 high value, biologically relevant markers in 225 drug metabolism enzyme, trans- porter, and transferase genes. Such informa- tion is useful in identifying the responders to drugs and is discussed further in sub- sequent chapters. Ethnic Differences in Drug Metabolism Ethnic differences in drug metabolism are well documented for a number of drugs. The molecular mechanisms responsible for ethnic differences in drug metabolism have been partly clariﬁed because of the advances in molecular biology. Genotype analysis indicates a different frequency for the mutant alleles in different ethnic populations, which results in variations in the frequency of subjects who are homo- zygous for the mutant allele among the extensive metabolizers in different ethnic populations. Ethnic differences in drug metabolism may result from differences in distribution of a polymorphic trait and mutations, which code for enzymes with abnormal activity which occur with altered frequency in different ethnic groups. Ethnic factors, therefore, are an important consideration in individualization of therapy. Gender Differences in Pharmacogenetics There are gender-related differences in pharmacokinetics, which may be related to pharmacogenetic differences in to drug-metabolizing enzymes. Other gender differences in pharmacokinetics may be due to ﬂuctuations in hormone levels in women with menstruation and pregnancy. Moreover, development of diseases such as heart disease and cancer may affect women differently from men. There is no data to support the efﬁcacy of statins in preventing heart attacks and stroke in women with hypercholesterolemia, partly because there have not been adequate representation of women in clinical Universal Free E-Book Store Role of Pharmacogenetics in Pharmaceutical Industry 115 trials as compared to men. Use of statins in women is associated with a higher rate of complications such as myositis and cognitive impairment. Statin therapy in women without cardiovascular disease is controversial, given the insufﬁcient evidence of beneﬁt. Participants included 6,800 women and 11, 000 men with high- sensitivity C-reactive protein and low-density lipoprotein cholesterol randomized to rosuvastatin versus placebo. Meta-analysis studies were randomized placebo- controlled statin trials with predominantly or exclusively primary prevention in women and sex-speciﬁc outcomes. This study demonstrated that in primary preven- tion rosuvastatin reduced cardiovascular disease events in women with a relative risk reduction similar to that in men, a ﬁnding supported by meta-analysis of pri- mary prevention statin trials. Role of Pharmacogenetics in Drug Safety Variability in drug response among patients is multifactorial, including environmen- tal, genetic, and disease determinants that affect the disposition of the drug. Children may be exposed to these drugs through in utero exposure during preg- nancy, through breast feeding, and through exposure during adolescence. Adverse Drug Reactions Related to Toxicity of Chemotherapy Neurotoxicity and myelotoxicity are well known adverse reactions of chemother- apy in cancer patients. Additionally, patients who were homozygous variant at the 2677 and 3435 loci had a signiﬁcantly greater percent decrease in absolute neutrophil count at nadir. Polymorphisms in the genes that code for drug-metabolizing enzymes, drug transporters, drug receptors, and ion channels can affect an individual’s risk of having an adverse drug reaction, or can alter the efﬁ- cacy of drug treatment in that individual. Mutant alleles at a single gene locus are the best studied individual risk factors for adverse drug reactions, and include many genes coding for drug-metabolizing enzymes. These genetic polymorphisms of drug metabolism produce the phenotypes of “poor metabolizers” or “ultrarapid metabolizers” of numerous drugs. The vast majority arise from classical polymorphism in which the abnormal gene has a prevalence of more than 1 % in the general population. Toxicity is likely to be related to blood drug concentration and, by implication, to target organ concentration as a result of impaired metabolism. The other type is rare and only 1 in 10,000 to 1 in 100,000 persons may be affected. Mutant alleles at a single gene locus are the best studied individual risk factors for adverse drug reactions, including the genes for N-acetyltransferases, thiopurine methyltransferase, dihydropyrimidine dehydro- genase, and cytochrome P450. However, pharmacogenetic factors rarely act alone; rather they produce a phenotype in concert with other variant genes such as those for receptors and with environmental factors such as cigarette smoking. Most idiosyncratic drug reactions are unpredictable and because of their rarity my not show up in patients during clinical trials with a few thousand patients. They may ﬁrst surface when the drug has been taken by hundreds of thousands of patients in the post-marketing phase. Pharmacogenetics, by individualizing treatment to patients for whom it is safe, provides a rational framework to minimize the uncer- tainty in outcome of drug therapy and clinical trials and thereby should signiﬁcantly reduce the risk of drug toxicity. Topiramate, an anticonvulsant medication, is an efﬁcacious treatment for alcohol dependence. Future studies in larger samples are needed to more fully establish these preliminary ﬁndings. In other situations, it may help in the adjustment of dose of the drug such as in warfarin therapy. Clinical signs include unexplained elevation of end-tidal Universal Free E-Book Store Role of Pharmacogenetics in Pharmaceutical Industry 119 carbon dioxide, muscle rigidity, acidosis, tachycardia, tachypnea, hyperthermia, and evidence of rhabdomyolysis. However, it is invasive, requiring skeletal muscle biopsy and is not widely available. Researchers have begun to map mutations within the ryanodine receptor gene (chromosome 19q13. Pharmacogenetics of Clozapine-Induced Agranulocytosis Clozapine has long been accepted as one of the most effective medications for treat- ing schizophrenia but has had limited utilization due to the risk of inducing agranu- locytosis, a life-threatening decrease of white blood cells that requires frequent blood testing of patients. This raised the hope for a one-time genetic test may obviate the need for continuous blood monitoring for the majority of clozapine- treated patients. These ﬁndings have uncovered new clues to the underlying biological and physiologic mechanisms of drug-induced agranulocytosis and provide a starting point for eluci- dating a common mechanism across drugs from different classes that carry this rare but devastating side effect. The sensitivity and selectivity of these biomarkers could support further development of a diagnostic test. However, no genetic test is currently available for clozapine-induced agranulo- cytosis. Candidate gene studies have failed to identify a strong, replicated genetic variant that substan- tially increases risk of clozapine-induced agranulocytosis. Combined analysis of such studies may identify associated genetic variants that can be rapidly translated to clinical practice. Universal Free E-Book Store 120 4 Pharmacogenetics Role of Pharmacogenetics in Warfarin Therapy Warfarin (Coumadin) is the most commonly prescribed oral anticoagulant for the treatment and prevention of thromboembolic events.
It is caused by Bartonella henselae and is frequently transmitted from cat scratches that penetrate the epidermis cheap 400mg carbamazepine muscle relaxant voltaren. In the ﬁrst phase of the disease purchase 200mg carbamazepine amex muscle relaxant shot, thyroid inﬂammation leads to follicle destruction and release of thyroid hormone generic carbamazepine 400mg online muscle relaxant 4211 v. In the second phase carbamazepine 100 mg with visa spasms video, the thyroid is depleted of hormone and hypothyroidism results. A recovery phase typically follows in which decreased inﬂammation allows the follicles to heal and regenerate hormone. Large doses of aspirin (such as 600 mg by mouth every 4–6 h) or nonsteroidal anti-in- ﬂammatory drugs are often sufﬁcient for what is usually a self-limited illness. Thyroid function should be monitored closely; some patients may require low-dose thyroid hormone replacement. The intensive group received multiple administra- tions of insulin daily along with education and psychological counseling. Improvement in glycemic control resulted in a 47% reduction in retinopathy, a 54% reduc- tion in nephropathy, and a 60% reduction in neuropathy. There was a nonsigniﬁcant trend toward improvement in macrovascular complications. Individuals receiving intensive glycemic control had a reduction in microvascular events but no signif- icant change in macrovascular complications. However, hypoparathyroidism may occur even if the parathyroid glands are not removed by thyroidectomy due to devascularization or trauma to the parathy- roid glands. Hypocalcemia following removal of the parathyroid glands may begin any time during the ﬁrst 24–72 h, and monitoring of serial calcium levels is recommended for the ﬁrst 72 h. The earliest symptoms of hypocalcemia are typically circumoral paresthesias and pares- thesias with a “pins-and needles” sensation in the ﬁngers and toes. The development of carpal spasms upon inﬂation of the blood pressure cuff is a classic sign of hypocalcemia and is known as Trousseau sign. Chvostek sign is the other classic sign of hypocalcemia and is elicited by tap- ping the facial nerve in the preauricular area causing spasm of the facial muscles. Maintenance therapy with calcitriol and vitamin D is necessary for ongoing treat- ment of acquired hypoparathyroidism. Alternatively, surgeons may implant parathyroid tissue into the soft tissue of the forearm, if it is thought that the parathyroid glands will be removed. Hypomagnesemia can cause hypocalcemia by suppressing parathyroid hormone release de- spite the presence of hypocalcemia. However, in this patient, hypomagnesemia is not sus- pected after thyroidectomy, and magnesium administration is not indicated. Benztropine is a centrally acting anticholinergic medication that is used in the treatment of dystonic reactions that can occur after taking centrally acting antiemetic medications with dopaminergic activity, such as metoclopramide or compazine. While this patient has taken a medication that can cause a dystonic reac- tion, the spasms that she is experiencing are more consistent with tetanic contractions of hy- pocalcemia than dystonic reaction. Finally, measurement of forced vital capacity is most commonly used as a measurement of disease severity in myasthenia gravis or Guillain-Barré syndrome. The presence of a secretory diarrhea is conﬁrmed by a stool osmolal gap [2(stool Na + stool K) – (stool osmo- lality)] <35 and persistence during fasting. The differential diagnosis includes gastrinoma, laxative abuse, carcinoid syndrome, and systemic mastocytosis. When hypercalcemia is severe (>15 mg/ dL), symptoms frequently include dehydration and altered mental status. Initial therapy includes large-volume ﬂuid admin- istration to reverse the dehydration that results from hypercalciuria. If the calcium remains elevated, as in this patient, additional measures should be undertaken to decrease the serum calcium. Calcitonin has a rapid onset of action with a decrease in serum calcium seen within hours. Pamidronate is a bisphosphonate that is useful for the hypercalcemia of malignancy. Thus, in this patient with ongoing severe symptomatic hypercalcemia, addition of both calcitonin and pamidronate is the best treatment. The addition of a thiazide diuretic is contraindicated because thiazides cause in- creased calcium resorption in the kidney and would worsen hypercalcemia. Primary dysmenorrhea results from increased stores and subsequent release of prostaglandin precursors. Secondary dysmenorrhea is caused by underlying pelvic pathology, the causes of which are many. The differential diagnosis includes endometriosis (ectopic en- dometrium), mittelschmerz (ruptured graaﬁan follicle), adenomyosis (ectopic endome- trial glands within the myometrium), and cervical stenosis. A history of sexual abuse correlates with dyspareunia more often than dysmenorrhea. It may represent a variation on the norm or be a prelude to a more serious underlying con- dition. Virilization refers to the state in which androgen levels are elevated enough to cause signs and symptoms of changes in voice, enlargement of genitalia, and increased libido. Vi- rilization is a concerning sign for an ovarian or adrenal cause of excess androgen produc- tion. This patient’s change in voice and body habitus heightens one’s concern about a virilizing process. A thorough medication history is indicated because drugs such as pheny- toin, minoxidil, and cyclosporine have been associated with androgen-dependent hair growth. Family history is critical as some families have a higher incidence of hirsutism than others do. Congenital conditions such as congenital adrenal hyperplasia can show distinct patterns of inheritance. An elevation in plasma total testosterone above 12 nmol/L usually indicates a virilizing tu- mor. Therefore, check- ing both levels is a useful initial hormonal screen in evaluating virilization. Although polycystic ovarian syndrome is by far the most common cause of ovarian androgen excess, initial screening with ultrasound is not recommended. Polycystic ovaries may be found in females without any evidence of excess androgen secretion. Likewise, females may have an ovarian source of androgen secretion with only slightly enlarged ovaries on ultrasound. Typically these patients will have normal pituitary function and should be reassured. It is likely that the surrounding rim of pituitary tissue is functioning normally. An empty sella may signal the insidious onset of hypopituitarism, and laboratory results should be followed closely. Endocrine malignancy is unlikely, and surgery is not part of the management of an empty sella. They are most common in children and often present with signs of increased intracranial pressure. Weight gain, cognitive changes, sleep disorders, and visual field defects are common.
Cunha Infectious Disease Division order carbamazepine 200 mg on line muscle relaxant wiki, Winthrop-University Hospital discount carbamazepine 400 mg without prescription muscle relaxant orphenadrine, Mineola generic carbamazepine 400mg amex muscle relaxant tablets, New York discount 400mg carbamazepine with mastercard ql spasms, and State University of New York School of Medicine, Stony Brook, New York, U. It is a common clinical misconception that antibiotics have the same resistance potential or that the resistance potential is related to antibiotic class. Attempts have been made to correlate structure–activity relationships with antibiotic resistance with different classes of antibiotics. This approach applies to relatively few antibiotic aminoglycosides, but not to the majority of antibiotics in other antibiotic classes. A historical approach to understanding antibiotic-associated resistance from a clinical standpoint indicates that some antibiotics are more likely to cause resistance than others. These antibiotics may be termed “high-resistance potential” antibiotics indicating the resistance potential is not necessarily high in terms of percentage but relatively higher than those with a “low-resistance potential. While antibiotics should not be used thoughtlessly, all other things being equal, it is always preferable to use an antibiotic with a low resistance potential, in preference to one with a high resistance potential. There is no good explanation for why within each antibiotic class there are one or more antibiotics that have high resistance potential while the others in the group with a similar structure and pattern/volume of use have not been associated with significant resistance problems. Low-resistance potential antibiotics have been used for decades without causing widespread resistance, i. Antibiotic-induced resistance, therefore, is not related to antibiotic class, volume, or duration of antibiotic use, but rather is an attribute of one or more antibiotics in each antibiotic class that may be considered as high-resistance potential antibiotics whereas the other antibiotics in the class may be termed low-resistance potential antibiotics. However, it should be remembered that if an institution has a resistance problem with a particular organism, i. All antibiotics with anti-pseudomonal activity in the institution must also be changed substituting anti-pseudomonal, low-resistance potential antibiotics for those on formulary that have a high antibiotic resistance potential. Therefore, in this case, not only should amikacin be substituted for gentamicin but meropenem must be substituted for imipenem, cefepime should be substituted ceftazidime, and levofloxacin substituted for ciprofloxacin. If multiple formulary substitutions are not implemented, the antibiogram of the institution will show increasing resistance among the low-resistance potential anti-pseudomonal antibiotics that have not replaced their high-resistance potential counterparts. In this setting, if amikacin is substituted for gentamicin but imipenem, ciprofloxacin, and ceftazidime usage continues, resistance problems will be manifested by the worsening susceptibility patterns of meropenem, levofloxacin, and cefepime. Intrinsic resistance refers to the lack of activity of an antibiotic against an isolate, e. In contrast, acquired antibiotic resistance refers to isolates that were once formally sensitive to an antibiotic that have subsequently become resistant and the resistance is related to antibiotic use not mutation, i. Acquired antibiotic resistance may be further subdivided into relative resistance and absolute or high-level resistance. Although reported as “resistant,” such an isolate may in fact be susceptible in body sites that concentrate the antibiotic to greater than serum levels, i. Pseudomonas is not an infrequent colonizer of the urine in patients with indwelling urinary catheters, i. These strains should be identified as such and their spread limited by effective infection-control containment measures. The reason for this is that colonizing strains exist in sites where the concentration of antibiotics may be subtherapeutic. All other things being equal, subtherapeutic concentrations of antibiotics are more likely to predispose to resistance than our supra therapeutic concentrations. It is important to differentiate colonization from infection to avoid needless antibiotic use (3–6). The incorrect clinical assumption is that the isolate in the respiratory secretions is reflective of the pathological process in the parenchyma of the lung. Respiratory secretions and parenchyma of the lung are rarely related and nearly always represent colonization rather than infection. In ventilated patients with fever and leukocytosis with a shift to the left and pulmonary infiltrates, it is well known that the cause of such patients’ pulmonary infiltrates is more commonly noninfectious than infectious. The necrotic/invasive nature of this fulminating/necrotic pneumonia is manifested by demonstrating elastin fibers using an elastin stain in respiratory secretions. Aminoglycosides concentrate the high concentration in the urine and are ideal agents to use in P. There are relatively few anti-pseudomonal antibiotics that are effective and reach therapeutic concentrations in the lung. Aminoglyco- sides have modest anti-Klebsiella activity but cephalosporins are highly active against K. Traditionally, double-drug antibiotic therapy was used to treat serious systemic K. Because *33% of tigecycline is excreted into the urine, therapeutic urinary concentrations may not be achievable with the usual tigecycline dosing, i. Acinetobacter colonization of aqueous solutions in respiratory support equipment is usually responsible for A. In excluding outbreaks, nearly always Acinetobacter isolates recover from respiratory secretions, represent colonization rather than infection indicative of A. This 518 Cunha can be achieved most simply by avoiding the unnecessary treatment of colonized respiratory secretions or urine (6,7,10). Pseudomonas aeruginosa susceptible only to colistin in intensive care unit patients. Efficacy and safety of colistin (colistimethate sodium) for therapy of infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii in Siriraj Hospital, Bangkok, Thailand. Intravenous polymyxin B for the treatment of nosocomial pneumonia caused by multidrug-resistant Pseudomonas aeruginosa. Colistin-resistant isolates of Klebsiella pneumoniae emerging in intensive care unit patients: first report of a multiclonal cluster. Extended spectrum beta-lactamase-producing Klebsiella pneumoniae chronic ambulatory peritoneal dialysis peritonitis treated successfully with Polymyxyin B. Surveillance cultures and duration of carriage of multidrug-resistant Acinetobacter baumannii. Emergence of resistant Acinetobacter baumannii in critically ill patients within an acute care teaching hospital and long-term acute care hospital. Clinical and economic impact of multidrug resistance in nosocomial Acinetobacter baumannii bacteremia. Polymyxin B and doxycycline use in patient with multidrug-resistance Acinetobacter baumannii infections in the intensive care unit. Post-neurosurgical meningitis due to multi-drug resistant Acinetobacter baumanii treated with intrathecal colistin: case report and review of the literature. Antimicrobial effects of varied combinations of meropenem, sulbactam, and colistin on a multidrug-resistant Acinetobacter baumannii isolate that caused meningitis and bacteremia. Antibiotic Kinetics in the Febrile 29 Multiple-System Trauma Patient in Critical Care Donald E. Fry Northwestern University Feinberg School of Medicine, Chicago, Illinois and Department of Surgery, University of New Mexico School of Medicine, Albuquerque, New Mexico, U. Judicious and appropriate antibiotics are important for preventive indications when the traumatized patient requires a surgical procedure. Specific antibiotic therapy is necessary when infectious complications occur at the site of injury. Nosocomial infections occur at numerous locations during the critical care management and during the prolonged convalescence of these patients, antimicrobial chemotherapy for treatment. In the patient with an injury severity score > 30, antibiotics are employed frequently during the hospitalization and the emergence of resistant and unusual pathogens make the appropriate management of the infectious complications of these patients a formidable challenge. The principals in the utilization of antibiotics for different indications in the trauma patient have become established over the last several decades.