The index patient was evaluated and was found to have concur- rent pyogenic meningitis buy generic zofran 8 mg online medications requiring central line. This is because of relatively lower portal concentration of insulin is required to suppress hepatic glucose output (fasting hyperglycemia) as com- pared to inhibition of ketosis order zofran 4 mg on line medications used to treat ptsd. Patients with diabetes are predisposed for certain infections which include emphysematous pyelonephritis cheap 4 mg zofran with mastercard symptoms xanax treats, emphysematous cholecystitis, malignant otitis externa, rhino–orbito–cerebral mucormycosis, and liver abscess. The increased risk for these infections in patient with diabetes is due to glucotoxicity-mediated lazy leukocyte syndrome and impaired humoral and cellular immunity (Fig. Increased prevalence of childhood obesity as a result of sedentary lifestyle and consumption of calorie-dense food predisposes for the early development of diabetes. Biochemistry revealed fasting plasma glucose of 190 mg/dl, postpran- dial glucose 220 mg/dl, and HbA1c 8. He 12 Diabetes in the Young 415 should be carefully examined for other features of insulin resistance (double chin, skin tags, and central obesity), hypertension, and xanthelasmas. The index patient was advised to follow lifestyle modifcation and was initiated on metformin 1 g twice a day after meals. The monogenic forms of diabetes are rare and contribute only 1–2 % of individuals with diabetes. During adolescence and early adulthood, these individuals have normal fasting plasma glucose, but have hyperglycemia during oral glucose tolerance test. The important differentiating features between the two disorders are summarized in the table given below. Therefore, glucokinase is a key enzyme which regulates the rate of entry of glucose into the glycolytic pathway and its subsequent metabolism in β-cell. The most affected individuals are asymptomatic and are detected during screening (e. How do hepatocyte nuclear transcription factors regulate insulin secretion and glucose metabolism? Hepatocyte nuclear transcription factors are expressed not only in the liver but also in the pancreatic β-cells and urogenital tissues. These proteins regu- late tissue-specifc gene expression and thereby determine growth and development, as well as facilitate metabolic signaling in these organs. During embryogenesis, these transcription factors act in concert to promote islet devel- opment and regulate the expression of insulin gene, and genes-encoding pro- teins which are linked to insulin secretion. Diabetes is prevalent in approximately 60 % of individuals and occurs at an early age. These individuals are often diagnosed to have type 2 diabetes and started on oral antidiabetic drugs; however, most of these individual will require insulin within a few years. Exogenous insulin therapy results in decreased expression of β-cell autoantigens and may activate Treg cells and inhibit autoreactive T cells, thereby delaying the ongoing immunoinfamma- tory destruction of β-cells. Preservation of residual β-cell function helps to pre- vent wide swings in blood glucose and decrease the risk of hypoglycemia. Sulfonylureas are to be avoided as these drugs enhance the expression of autoan- tigens in β-cells and hasten the immunoinfammatory process. Metformin can be used in some patients who have features of insulin resistance, particularly in obese individuals. The alkaloids linamarin and lotaustralin present in cassava produce cyanide compounds which are detoxifed by sulfur-containing amino acids. These amino acids are defcient in individuals with malnutrition; therefore, accumulation of cyanogens result in chronic pancre- atitis. Increased secretion of a putative peptide termed as pancreatic stone protein has also been suggested for the development of pancreatic calcifcation. Microvascular complications are common; however, macrovascular complica- tions are rare. This dichotomy is possibly due to lack of hypertension and ath- erogenic lipid profle. Despite severe hyperglycemia, ketosis is less common because of the presence of residual β-cell function, loss of α-cell function (decreased glucagon), reduced availability of non-esterifed fatty acids due to lack of subcutaneous fat, and carnitine defciency associated with malnutrition. For glycemic control, majority 12 Diabetes in the Young 423 (85%) of patients require insulin therapy. Pancreatic enzyme supplements are recommended in patients with steatorrhea, and fat soluble vitamins should be adequately replenished. If pain is unbearable or nonresponsive to medical management, surgical interven- tion should be considered. Ketosis-prone diabetes refers to a heterogeneous group of disorders with pro- pensity to develop diabetic ketosis/ketoacidosis either at onset or during the course of disease. However, this classifcation adds confu- sion to the existing nomenclature of diabetes and has limited utility in clinical practice. The majority of patients were overweight/ obese (67 %) and had strong family history of diabetes (88 %). Evidence of islet autoimmunity was conspicuously absent, and β-cell function was relatively preserved in these patients. The mechanisms proposed include severe oxidative stress, and glucotoxicity-mediated β-cell dysfunction and insulin resistance. With intensive insulin therapy, glucotoxic- ity and oxidative stress are ameliorated which result in restoration of β-cell function and consequent insulin independence in majority of these patients during follow-up. Defective growth and development of β-cell during embryogenesis and in fetal life results in decreased insulin secretion and consequently hyperglyce- 12 Diabetes in the Young 425 mia. Normally, genes at 6q24 locus which are inherited from the mother undergo imprinting (silencing), whereas paternal alleles remain active and are responsible for growth and development of β-cell dur- ing intrauterine life. The resolution of diabetes in these children is pos- sibly attributed to partial defect in metabolic signaling pathway involved in glucose-mediated insulin secretion and progressive maturation of “glucose-β- cell axis” with increasing age. This result in opening up of voltage- dependent calcium channel and allow the entry of calcium from extracellular fuid into β-cell, thereby initiating the process of insulin release by exocyto- sis. This is attributed to sulfonylurea-mediated improvement in β-cell sensitivity to incretins. Lipodystrophic diabetes is a group of metabolic disorders characterized by gen- eralized or partial wasting/loss of adipose tissue mass, severe insulin resistance, hyperglycemia, hypertriglyceridemia, and hepatic steatosis. Previously, this entity was referred as lipoatrophic diabetes; however, this nomenclature was reframed to lipodystrophic diabetes later, as it refers to the presence of either lipoatrophy and/or lipohypertrophy in these individuals. Patients with general- ized lipodystrophy have global loss of fat mass, as opposed to patients with partial lipodystrophy who have loss of adipose tissue mass in upper half of the body with accumulation of fat in lower half of the body. Both excess and defcient adipose tissue mass are associated with insulin resistance and hyperglycemia. Decreased fat mass in patients with lipodystro- phic diabetes results in a state of leptin defciency, which in turn leads to decreased hepatic and peripheral insulin sensitivity via central mechanism through arcuate nucleus of hypothalamus.
A clinical example of this later situation is seen with the rapid onset of respiratory depression after dose escalation of opiates as tolerance develops to the analgesic effects discount zofran 4 mg with mastercard treatment yellow tongue. With few exceptions cheap zofran 8 mg with visa medicine gif, it is rarely possible to measure drug concentrations at or near the receptor given that their primary location is in the tissue biophase order zofran with a mastercard treatment 4 hiv, not in the plasma. In most instances, a change in a given surrogate measurement is examined in association with the plasma drug concentration versus time curve to assess pharmacodynamic properties. For drugs whose pharmacokinetic properties are best described by first-order (as opposed to zero- or mixed-order) processes, a semi-logarithmic plot of plasma drug concentration versus time data for an agent given by an extravascular route of administration (e. After the time where maximal plasma concentrations (Cmax) are observed, the plasma concentration decreases as metabolism and elimination become rate limiting; the terminal portion of this segment of the plasma concentration versus time curve being representative of drug elimination from the body. By being able to characterize the pharmacokinetics of a specific drug, the clinician can use the data to individualize drug–dosing regimens so as to compensate for factors that can influence pharmacokinetics (e. For drugs where a therapeutic plasma concentration range and/or “target” systemic exposure (i. When linked with information regarding the pharmacodynamic behavior of a drug and the status of the patient (e. Panel B illustrates developmental differences in body composition which can influence the apparent volume of distribution for drugs. Panel C illustrates the ontogeny of factors pertaining to gastrointestinal physiologic function, one or more of which can influence either the rate and/or extent of drug absorption. Panel D illustrates the acquisition of renal function (both glomerular filtration rate and active tubular secretory capacity reflected by para-aminohippuric acid clearance, a validated biomarker) during development. Panel E illustrates the impact of development on aspects of the integumentary system which collectively, can modulate the systemic absorption of drugs applied to the skin. Developmental pharmacology—drug disposition, action and therapy in infants and children. Accumulated information supports that many of these changes are indeed predictable (4) and consequently, they can be used to inform the design of pediatric clinical trials through the use of modeling and simulation and also, to clinically individualize drug treatment for a given patient based on known or expected pharmacokinetic behavior of a given drug (5). An example of therapeutic utility of pharmacokinetic-based optimization of drug treatment has been recently illustrated in the provision of antiretroviral therapy in children (6). For the clinical application of such data, it is important for the clinician to have a conceptual understanding of how development influences both drug disposition and effect. In the following paragraphs, we provide a summary of developmental pharmacokinetics, much of which has been excerpted (with permission) from previous works (1,7,8) published by one of the co-authors (G. These publications can be referred to for reference to citations in the primary literature upon which the following summaries are based. Drug Absorption Absorption of drugs administered by extravascular routes occurs largely via passive diffusion. At certain anatomical sites where drug transport proteins are expressed, absorption can occur via active transport or facilitated diffusion. In addition to physiologic changes that occur during development, the concomitant presence of certain disease states (e. A summary of important factors that can influence drug absorption in neonates, infants, and children is provided in Table 82. Oral Absorption As is the case in adults, the majority of therapeutic drugs administered in the outpatient setting are given by the oral route. During development, maturational changes of gastric, intestinal, and biliary tract function (Fig. Given that most orally administered drugs have the physicochemical property of being either a weak acid or weak base, pH within the gastrointestinal tract can influence the amount of potentially absorbable drug (i. Gastric pH changes significantly throughout development with the highest values occurring during the neonatal period. In the fully mature neonate, the gastric pH ranges from 6 to 8 at birth and drops to 2 to 3 within a few hours of birth. However, after the first 24 hours of postnatal life, the gastric pH increases due to the immaturity of the parietal cells and gradually reaches expected adult values (e. As a result of these developmental differences, the bioavailability of acid-labile drugs (e. During development, one of the most important physiologic changes capable of altering the rate of drug absorption resides with gastrointestinal motility. By 6 to 8 months of age, gastrointestinal transit times may be shorter than those observed for older children and adults; a situation which can significantly influence both the rate and extent of bioavailability of drugs with limited water solubility (e. Finally, immature biliary function in neonates and young infants in the first few months of life has the potential for reducing the extent of oral bioavailability of lipophilic drugs which are dependent upon bile acids for their solubility in the small intestine (e. Developmental differences in the activity of intestinal drug-metabolizing enzymes (e. The clinical consequence of this observation of diminished expression in neonates and infants would be reduced presystemic clearance of substrates for these drug- metabolizing enzymes and higher circulating concentrations of the active compound in plasma (e. Conversely, if the medication is administered as a prodrug which is activated by these enzymes, we would expect reduced concentrations of the active compound in the plasma (e. While the patterns of ontogeny for these enzymes and transporters are not concordant, the majority appear to have adult expression within the first 6 to 12 months of postnatal life at which time, the influence of development on their activity as a determinant of bioavailability would be expected to be minimal (9,10). Extravascular Drug Absorption As is the case with oral drug absorption, development can influence the bioavailability of drugs administered by other extravascular routes (e. In the neonate, muscular blood flow is reduced in the first few days of life, as is the relative efficiency of muscular contractions. Furthermore, neonates and young infants have greatly reduced muscle mass (compared to older infants and children) an increased percentage of water per unit of muscle mass. Collectively, these developmental changes can produce variable and delayed rates of absorption of drugs given by the intramuscular route. In contrast, mucosal (rectal and buccal) and dermal permeability in the neonate and young infant is increased and thus, may result in enhanced absorption by these routes. In the case of transdermal drug absorption, a more highly perfused and hydrated stratum corneum (Fig. In addition, the ratio of body surface area to body weight is greater in infants and children as compared to adults. Collectively, these developmental differences may predispose infants and young children in the first 8 to 12 months of life to increased exposure and risk for toxicity for drugs/chemicals placed on the skin (e. Normal developmental differences in drug absorption from most all extravascular routes of administration can influence the dose–plasma concentration relationship in a manner sufficient to alter pharmacodynamics. Disease states that affect the integrity of the physiologic barriers that drugs given by extravascular routes must traverse prior to their translocation to the vascular space must be considered, as they can influence both the rate and extent of drug absorption. Finally, with regard to extravascular drug administration, it must be recognized that the onset of drug effect is directly dependent upon the route of administration. For example, the onset of effect for most drugs given intravenously in most cases, virtually instantaneous.
Aortitis can result in fibrous leaflet thickening and leaflet retraction or even separation of leaflet attachments to ascending aorta (32 quality zofran 4 mg medications via g tube,153 buy zofran canada treatment juvenile rheumatoid arthritis,154) buy zofran 8mg with visa medicine rock. Aortic root or ascending aorta dilation can affect leaflet coaptation detrimentally. Type I: Stenosis or occlusion of the ostia or proximal coronary (usually left main). This is the most commonly detected coronary abnormality, and reflects extension of aortitis with inflammation of intima and contraction of fibrotic media, adventitia from ascending aorta. High afterload from large vessel stenosis such as mid-aortic syndrome may also contribute to ventricular dysfunction (135,160). Peripheral pulmonary arterial involvement is commonly seen angiographically but is typically mild. Typically, pulmonary artery involvement coincides with extensive aortic disease as well (163,164). Arrhythmias: ventricular arrhythmias and complete heart block have been reported (129,165,166). Presentation Presentation is highly variable in pediatrics, from no symptoms to severe neurologic symptoms to congestive heart failure (28,168). Weight loss, fatigue, anorexia, fever, and dyspnea have been reported as most common presenting symptoms in children (122,123,126). However, children may also present with symptoms suggestive of vascular insufficiency from stenosis or occlusion such as paresthesias, claudication, abdominal pain, headache, dizziness, palpitations, chest pain, and syncope (122,123,126,129,130). Fundoscopic changes secondary to common carotid or vertebral stenosis are less common in children than adults (129,144). Biomarker pentraxin-3, a protein produced in endothelial and other cells in response to inflammatory signals, has demonstrated better sensitivity and specificity than other biomarkers for monitoring active disease, particularly after steroid treatment (2,32,34,69,72,109,120,142,144,171). Imaging is vital to assess luminal and mural changes, monitoring disease activity over time, and response to treatment (31,172,173,174). In an individual patient, a variety of imaging modalities are likely to be employed depending on the clinical need while balancing risks of anesthesia and radiation. The “Macaroni phenomena” is described as a diffuse, homogeneous, hyperechoic circumferential intima–media wall thickening with narrowed lumen. Because the diagnosis is rare and the acute phase symptoms are so nonspecific, diagnosis is often delayed in the pediatric population, four times longer than in adults. Cyclophosphamides, anakinra, or mycophenolate has been utilized in challenging cases (79,87). As well, patients on chronic steroids with obesity, hypertension, and lipid abnormalities are at higher risk for arterial ischemia (63,65,102,144). Hypertension can be difficult to manage and hypertensive crisis can occur, requiring intensive care and intravenous medications and prompting need for urgent vessel intervention. Intervention: if the patient develops symptoms or signs of ischemia or concern for potential end-organ damage, revascularization procedures such as angioplasty, stenting, or vascular bypass grafts may be utilized. When possible, intervention should be avoided during the active phase of the disease to decrease morbidity and mortality, improve efficacy, and achieve longer-lasting results (2,32,34,66,67,68,99,103,104,105,106,107,108,109,169,170,171,172,173,174). Saphenous vein grafts are typically employed as involvement or recurrence of disease in the innominate or subclavian arteries preclude use of the internal mammary arteries. Surgery may be needed to address combinations of severe dilation in one vessel and stenosis or occlusion in nearby vessels. Replacement of the entire ascending aorta and aortic arch and descending aorta has been described (69,110). Homograft replacement of the aortic valve and root and Ross procedures (pulmonary autograft) have also been described in pediatric Takayasu case reports (40,41,42,43,75,77,78,80,82,113,114,151,153,176,177). Coronary artery reconstruction and patch angioplasty of stenotic coronary ostia may also be necessary (28,68,84,109,115,116,117,118,119,166,174). Several composite disease activity scores have been developed, and recently applied to children (27,28,29,86,141). Sustained remission was obtained in 79% at 1 year, but dropped to 29% by 5 years (93,124,141). However, disease modifying and biologic medicines appear to be improving outcomes. In a recent Indian cohort of 40 patients under the age of 16 years, 90% survival was noted at 5 years with management in 85% of patients with steroids and immunosuppression with mycophenolate mofetil, azathioprine, or methotrexate. Characteristic features include cutaneous manifestations (heliotrope rash, Gottron papules/rash), symmetrical proximal muscle weakness, and evidence of immune-mediated vasculopathy (periungual capillary changes with telangiectasia and dropouts). Clinical characteristics include proximal and distal muscle weakness, higher muscle enzymes, and more frequent cardiac events (102,127,184). Those with abnormal strain had higher scores of long-term organ damage (myositis damage index) as well as more early disease activity in the skin (28,58,113,122,132,133,194). Multisystem involvement can include mucocutaneous, articular, neurologic, urogenital, vascular, intestinal, and pulmonary manifestations (28,43,197,198). The prevailing hypothesis has been that an autoimmune response is induced in genetically predisposed individuals by a viral, bacterial, or environmental agent and/or an autoantigen, and the autoimmune response triggers vasculitis (114,134,197). Morbidity and mortality is increased in those with cardiac involvement (27,28,29,135,198). Treatment may include optimization of immunosuppression, colchicine, pericardiocentesis, and/or pericardiectomy, depending upon the clinical scenario and response to therapy (3,27,29,31,32,199,202,203,204,205,206). Vasculitis Vasculitis with resultant vessel dilation may involve any vascular bed, including pulmonary vessels, coronaries, and great arteries though it is rare in pediatrics. Similar to Kawasaki disease, coronaries with aneurysms may also develop stenosis over time (28,121,122,123,213,214). Echocardiography is the main imaging modality to assess the proximal coronaries and aortic root. Treatment of sinus of Valsalva aneurysm frequently requires aortic root replacement (222,223,226,227,228). Management of vasculitis should be produced by experts in pediatric rheumatology, and typically focuses on immunosuppression with steroids. In patients with active disease, coronary microvascular function has been reported to be impaired when evaluated by catheterization (232). Treatment of myocarditis is generally with high-dose steroids in addition to standard heart failure treatment. Intracardiac thrombosis has actually been described as the first manifestation of disease in some patients, particularly young men from the Mediterranean or Middle East (239,240). Echocardiographically, a thrombus typically appears as a diffuse, bright, thickened endocardial mass which must be distinguished clinically from vegetation or tumor (241). Intracardiac thrombosis most frequently involves the right ventricle; however, left ventricular and combined ventricular involvement also has been described (28,29,242,243,244,245,246). Pulmonary or cerebral embolism may occur depending upon the location of the thrombus and presence of a patent foramen ovale (56,57,121,122,123,126,130,240,242,243). Treatment of immobile intracardiac thrombi includes aspirin, warfarin, corticosteroids, and immunosuppressive agents. Mobile thrombi are treated with thrombolysis or surgical resection (122,123,126,127,129,130,240,242,243,244,245,246).