Robert L. Benz MD, FACP

• Clinical Professor of Medicine, Jefferson Medical College, Philadelphia,
• Pennsylvania
• Chief, Division of Nephrology, Main Line Health System
• Nephrology
• Fellowship Director, Lankenau Hospital, Wynnewood, Pennsylvania

However spasms hip order discount shallaki line, unbuffered muscle relaxant 563 cheap shallaki 60 caps on line, regular insulin (500 units/mL) is for subcutaneous injection only and should not be given by intravenous or intramuscular injection spasms bladder order 60caps shallaki with mastercard. The short-acting insulin analogues Goals should be individualized for each patient and may be different for certain patient populations (lower or higher) muscle relaxant with least side effects generic 60 caps shallaki with visa. More detailed recommendations can be found in American Diabetes Association spasms headache buy shallaki cheap online, 2017 spasms in 6 month old baby trusted 60 caps shallaki. Subcutaneous administration of insulin delivered into the peripheral circulation can lead to near-normal glycemia but differs from physiological secretion of insulin in two major ways: the absorption kinetics do not reproduce the rapid rise and decline of endogenous insulin in response to changes in blood glucose. Thus, the portal/peripheral insulin concentration is not physiological, and this may alter the influence of insulin on hepatic metabolism. When used to treat glycemia after meals, the short-acting analogues have lower rates of hypoglycemia and modestly improved A1c levels compared to regular insulin. Unlike regular insulin, lispro dissociates into monomers almost instantaneously following injection. This property results in the characteristic rapid absorption and shorter duration of action compared with regular insulin. Insulin aspart is formed by the replacement of proline at B28 with aspartic acid, reducing self-association. Like lispro, insulin aspart dissociates rapidly into monomers following injection. Insulin glulisine is formed when glutamic acid replaces lysine at B29 and lysine replaces asparagine at B3; these substitutions result in a reduction in self-association and rapid dissociation into active monomers. Doses and concentrations of clinically used insulin preparations are expressed in international units. Pharmacopeia unit as the amount required to reduce the blood glucose concentration to 45 mg/dL (2. Most preparations of insulin are supplied in solution or suspension at a concentration of 100 units/mL, which is about 3. Insulin also is available in more concentrated preparations (200 [degludec and lispro insulins], 300 [glargine insulin], or 500 [regular insulin] units/mL) for patients who are resistant to the hormone and require higher doses. This produces a cloudy or whitish solution in contrast to the clear appearance of other insulin solutions. Two arginine residues are added to the C terminus of the B chain, and an asparagine molecule in position 21 on the A chain is replaced with glycine. When injected into the neutral pH of the subcutaneous space, aggregation occurs, resulting in prolonged, predictable, absorption from the injection site. Glargine may be administered at any time during the day with equivalent efficacy and does not accumulate after several injections. Insulin detemir is an insulin analogue modified by the addition of a saturated fatty acid to the amino group of LysB29, yielding a myristoylated insulin. When insulin detemir is injected subcutaneously, it binds to albumin via its fatty acid chain. The absorption profiles of glargine and detemir insulin are similar, but detemir often requires twice-daily administration. Insulin degludec is a modified insulin with one amino acid deleted (threonine at position B30) and is conjugated to hexadecanedioic acid via -l-glutamyl spacer at the amino acid lysine at position B29. Degludec, which is active at a physiologic pH, forms multihexamers after injection subcutaneously. Reversing amino acids 28 and 29 in the B chain (lispro) or substituting Asp for Pro28B (aspart) gives analogues with reduced tendencies for molecular self-association that are faster acting. Altering Asp3B to Lys and Lys29B to Glu produces an insulin (glulisine) with a more rapid onset and a shorter duration of action. Substituting Gly for Asn21A and lengthening the B chain by adding Arg31 and Arg32 produces a derivative (glargine) with reduced solubility at pH 7. Deleting Thr30B and adding a myristoyl group to the -amino group of Lys29B (detemir) enhances reversible binding to albumin, thereby slowing transport across vascular endothelium to tissues and providing prolonged action. When degludec is injected subcutaneously, it forms multihexameric complexes that slow absorption; degludec also binds well to albumin; these two characteristics contribute to the prolonged effect of degludec (>24 h at steady state). Inhaled insulin (Afrezza) is formulated for inhalation using a manufacturer-specific device (Leahy, 2015). This formulation should be used in combination with a long-acting insulin and has a more rapid onset and shorter duration than injected insulin analogues. Jet injector systems that enable patients to receive subcutaneous insulin injections without a needle are available. Intravenous infusions of insulin are useful in patients with ketoacidosis or when requirements for insulin may change rapidly, such as during the perioperative period, during labor and delivery, and in intensive care situations. Long-acting insulin should not be given intravenously or intramuscularly or in an infusion device. Panel C shows the insulin level attained following subcutaneous insulin (short-acting insulin analogue) by an insulin pump programmed to deliver different basal rates. Short-acting insulins are the only form of the hormone used in subcutaneous insulin infusion devices. Insulin infusion devices provide a constant basal infusion of insulin and have the option of different infusion rates during the day and night to help avoid the rise in blood glucose that occurs just prior to awakening from sleep (the dawn phenomenon) and bolus injections that are programmed according to the size and nature of a meal. Pump insulin infusion devices can produce a more physiological profile of insulin replacement during exercise (where insulin production is decreased) and thus less hypoglycemia than traditional subcutaneous insulin injections provide. The technology for combining an insulin infusion device and continuous glucose monitoring is rapidly evolving with algorithms that alter the infusion rate (Thabit and Hovorka, 2016). Insulin administered as a single daily dose of long-acting insulin, alone or in combination with short-acting insulin, is rarely sufficient to achieve euglycemia. More complex regimens that include multiple injections of long-acting or short-acting insulin are needed to reach this goal. In all patients, careful monitoring of therapeutic end points directs the insulin dose used. In patients who have gastroparesis or loss of appetite, injection of a short-acting analogue postprandially, based on the amount of food actually consumed, may provide smoother glycemic control. Adverse Events Factors That Affect Insulin Absorption Factors that determine the rate of absorption of insulin after subcutaneous administration include the site of injection, the type of insulin, subcutaneous blood flow, smoking, regional muscular activity at the site of the injection, the volume and concentration of the injected insulin, and depth of injection (insulin has a more rapid onset of action if delivered intramuscularly rather than subcutaneously). Increased subcutaneous blood flow (brought about by massage, hot baths, or exercise) increases the rate of absorption. Rotation of insulin injection sites is recommended to avoid or limit subcutaneous scarring, lipohypertrophy, or lipoatrophy. Hypoglycemia is the major risk that must be weighed against benefits of efforts to normalize glucose control. Insulin treatment of both type 1 and type 2 diabetes is associated with modest weight gain. Although uncommon, allergic reactions to recombinant human insulin may still occur as a result of reaction to the small amounts of aggregated or denatured insulin in preparations, to minor contaminants, or because of sensitivity to a component added to insulin in its formulation (protamine, Zn2+, etc. Atrophy of subcutaneous fat at the site of insulin injection (lipoatrophy) was a rare side effect of older insulin preparations. Lipohypertrophy (enlargement of subcutaneous fat depots) has been ascribed to the lipogenic action of high local concentrations of insulin. For most patients, insulin-replacement therapy includes long-acting insulin (basal) and a short-acting insulin to provide postprandial needs. In a mixed population of patients with type 1 diabetes, the average dose of insulin is usually 0. A supplemental scale of short-acting Intravenous administration of insulin is most appropriate in patients with ketoacidosis or severe hyperglycemia with a hyperosmolar state (Umpierrez and Korytkowski, 2016). Insulin infusion inhibits lipolysis and gluconeogenesis completely and produces near-maximal stimulation of glucose uptake. In most patients with diabetic ketoacidosis, blood glucose concentrations will fall by about 10% per hour; the acidosis is corrected more slowly. As treatment proceeds, it often is necessary to administer glucose along with the insulin not only to prevent hypoglycemia but also to allow clearance of all ketones. Patients with a nonketotic hyperglycemic hyperosmolar state may be more sensitive to insulin than are those with ketoacidosis. Appropriate replacement of fluid and electrolytes, particularly K+, is an integral part of the therapy in both situations because there is always a major K+ deficit. A long-acting insulin should be administered subcutaneously before the insulin infusion is discontinued. Treatment of Diabetes in Children or Adolescents Diabetes is one of the most common chronic diseases of childhood, and rates of type 1 diabetes in American youth are estimated at 1 in 300. An unfortunate corollary of the growing rates of obesity over the past three decades 874 is an increase in the numbers of children and adolescents with non-autoimmune, or type 2, diabetes. In children and adolescents with type 1 diabetes, the recommended A1c goal is less than 7. Insulin infusion devices and continuous glucose monitoring are being used with increasing frequency in the pediatric diabetic population and in older children and adolescents. Because of the association of type 2 diabetes with obesity in the pediatric age group, lifestyle management is the recommended first step in therapy. Goals of reducing body weight and increasing physical activity are broadly recommended. Metformin is approved for children as young as 10 years of age and is available in a liquid formulation (100 mg/mL). Insulin is the typical second line of therapy after metformin; basal insulin can be added to oral agent therapy or multiple daily injections can be used when simpler regimens are not successful. Weight gain is a more significant problem than hypoglycemia with insulin treatment in pediatric type 2 diabetes. Some are available in an extended-release (glipizide) or a micronized (glyburide) formulation. The acute administration of sulfonylureas to patients with type 2 diabetes increases insulin release from the pancreas. With chronic administration, circulating insulin levels decline to those that existed before treatment, but despite this reduction in insulin levels, reduced plasma glucose levels are maintained. The absence of acute stimulatory effects of sulfonylureas on insulin secretion during chronic treatment is attributed to downregulation of cell surface receptors for sulfonylureas on the pancreatic cell. The liver metabolizes all sulfonylureas, and the metabolites are excreted in the urine. Thus, sulfonylureas should be administered with caution to patients with either renal or hepatic insufficiency. Sulfonylureas are used to treat hyperglycemia in type Management of Diabetes in Hospitalized Patients Hyperglycemia is common in hospitalized patients. Stress of illness has been associated with insulin resistance, possibly the result of counterregulatory hormone secretion, cytokines, and other inflammatory mediators. Food intake is often variable due to concurrent illness or preparation for diagnostic testing. Medications used in the hospital, such as glucocorticoids or dextrose-containing intravenous solutions, can exacerbate tendencies toward hyperglycemia. Finally, fluid balance and tissue perfusion can affect the absorbance of subcutaneous insulin and the clearance of glucose. Therapy of hyperglycemia in hospitalized patients needs to be adjusted for these variables. Emerging data indicate that hyperglycemia portends poor outcomes in hospitalized patients. Insulin is the cornerstone of treatment of hyperglycemia in hospitalized patients. In noncritically ill hospitalized patients, a basal plus bolus correction insulin regimen, adjusted for oral intake, is optimal (Jacobi et al. For critically ill patients and those with variable blood pressure, edema, and tissue perfusion, intravenous insulin is the treatment of choice. Intravenous administration of insulin also is well suited to the treatment of diabetic patients during the perioperative period and during childbirth. The second, more potent, generation of hypoglycemic sulfonylureas includes glyburide Dose should be lower in some patients. This may occur as a result of a change in drug metabolism or more likely from a progression of cell failure. Contraindications to the use of these drugs include type 1 diabetes, pregnancy, lactation, and, for the older forms, significant hepatic or renal insufficiency. Lessfrequent side effects include nausea and vomiting, cholestatic jaundice, agranulocytosis, aplastic and hemolytic anemias, generalized hypersensitivity reactions, and dermatological reactions.

Of note muscle relaxant stronger than flexeril generic shallaki 60 caps fast delivery, no significant differences were observed in outcome between long-acting nitrates spasms after bowel movement buy shallaki online, Ca2+ channel blockers muscle relaxant uk discount shallaki 60caps without a prescription, and blockers muscle relaxant images discount shallaki 60 caps without a prescription. Blockers can block the baroreceptor-mediated reflex tachycardia and positive inotropic effects that may occur with nitrates spasms after bowel movement order 60 caps shallaki overnight delivery, whereas nitrates spasms jaw buy discount shallaki, by increasing venous capacitance, can attenuate the increase in left ventricular end-diastolic volume associated with -blockade. Concurrent administration of nitrates also can alleviate the increase in coronary vascular resistance associated with blockade of adrenergic receptors. Ranolazine and trimetazidine have a direct effect on the myocardium and likely act independently of hemodynamic effects. They can therefore be well combined with all other antianginal drugs where permitted. Ivabradine is a possible alternative to blockers but is associated with toxicity when added to blockers, verapamil, or diltiazem (Fox et al. In severe exertional or vasospastic angina, the combination of a nitrate and a Ca2+ channel blocker may provide additional relief over that obtained with either type of agent alone. Because nitrates primarily reduce preload, whereas Ca2+ channel blockers reduce afterload, the net effect on reduction of O2 demand should be additive; however, excessive vasodilation and hypotension can occur. The latter diagnosis is essentially based on the presence or absence of increases in plasma levels of cardiac troponin (I or T). The term unstable angina pectoris is used for angina symptoms that present for the first time, change their usual pattern, occur at rest, or are resistant to nitrates. Source: Adapted from the European Society for Cardiology Guidelines; for details, see Montalescot et al. The most important interventions are as follows: Antiplatelet agents, including aspirin and thienopyridines. Nitrates are useful in reducing vasospasm and in reducing myocardial O2 consumption by decreasing ventricular wall stress. Intravenous administration of nitroglycerin allows high concentrations of drug to be attained rapidly. Because nitroglycerin is degraded rapidly, the dose can be titrated quickly and safely using intravenous administration. If coronary vasospasm is present, intravenous nitroglycerin is likely to be effective, although the addition of a Ca2+ channel blocker may be required to achieve complete control in some patients. The mainstay in these patients is immediate reperfusion by primary angioplasty and stenting or, in the absence of invasive options, fibrinolytic therapy. These patients have a better long-term prognosis and benefit less from early invasive procedures and intensified antiplatelet therapy. Mainstays are blockers and nitrovasodilators (in the absence of contraindications such as hypotension). Interestingly, neither intensive treatment of diabetes mellitus nor antihypertensive therapy appears to alter the progression of symptoms of claudication. Other risk factor and lifestyle modifications remain cornerstones of therapy for patients with claudication; physical exercise, rehabilitation, and smoking cessation (possibly supported by drug treatment with varenicline or bupropion) have proven efficacy. Drugs used specifically in the treatment of lower extremity claudication include pentoxifylline and cilostazol. Pentoxifylline is a methylxanthine derivative that is called a rheologic modifier for its effects on increasing the deformability of red blood cells. However, the effects of pentoxifylline on lower extremity claudication appear to be modest and not sufficiently supported by prospective evidence (Salhiyyah et al. Cilostazol has been mainly studied in Asian populations and seems to improve symptoms of claudication, but the effect on cardiovascular mortality remains unclear (Bedenis et al. Milrinone therapy was associated with an increase in sudden cardiac death, and the oral form of the drug was withdrawn from the market. Cilostazol therefore is labeled as being contraindicated in patients with heart failure, although it is not clear that cilostazol itself leads to increased mortality in such patients. Cilostazol has been reported to increase nonsustained ventricular tachycardia; headache is the most common side effect. Other treatments for claudication, including naftidrofuryl, propionyl levocarnitine, and prostaglandins, have been explored in clinical trials, and there is some evidence that some of these therapies may be efficacious. The pathways that lead to "in-stent restenosis" are complex, but smooth muscle proliferation within the lumen of the stented artery is a common pathological finding. Local antiproliferative therapies at the time of stenting have been explored over many years; several drug-eluting stents and, more recently, biodegradable stents have been introduced in the market. The drugs currently used in intravascular stents are paclitaxel, sirolimus (rapamycin), and the two sirolimus derivatives everolimus and zatarolimus. Paclitaxel is a tricyclic diterpene that inhibits cellular proliferation by binding to and stabilizing polymerized microtubules. Paclitaxel and sirolimus differ markedly in their mechanisms of action but share common chemical properties as hydrophobic small molecules. Many patients with advanced peripheral arterial disease are more limited by the consequences of peripheral ischemia than by myocardial ischemia. In the cerebral circulation, arterial disease may be manifest as stroke or transient ischemic attacks. The painful symptoms of peripheral arterial disease in the lower extremities (claudication) typically are provoked by exertion, with increases in skeletal muscle O2 demand exceeding blood flow that is impaired by proximal stenoses. When flow to the extremities becomes critically limiting, peripheral ulcers and rest pain from tissue ischemia can become debilitating. The inhibition of cellular proliferation by paclitaxel and sirolimus or derivatives not only affects vascular smooth muscle cell proliferation but also attenuates the formation of an intact endothelial layer within the stented artery and thereby markedly reduces the rate of restenosis compared with bare metal stents. Dual antiplatelet therapy (aspirin, typically with clopidogrel) is recommended for one year after intracoronary stenting with drug-eluting stents, similar to bare metal stents. Quantitative analysis of vascular to cardiac selectivity of L- and T-type voltage-operated calcium channel antagonists in human tissues. Clinical outcomes with beta-blockers for myocardial infarction: a meta-analysis of randomized trials. Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. Collateral and collateral-adjacent hyperemic vascular resistance changes and the ipsilateral coronary flow reserve. Documentation of a mechanism causing coronary steal in patients with coronary artery disease. Prognostic value of dipyridamole stress cardiovascular magnetic resonance imaging in patients with known or suspected coronary artery disease. The mechanisms of nitroglycerin action: stenosis vasodilatation as a major component of the drug response. The bioavailability and pharmacokinetics of slow release nifedipine during chronic dosing in volunteers. Selective inhibition of myocardial contractility by competitive divalent Ca++ antagonists (iproveratril, D 600, prenylamine) [in German]. Selectivity scale of calcium antagonists in the human cardiovascular system based on in vitro studies. Diltiazem treatment for pre-clinical hypertrophic cardiomyopathy sarcomere mutation carriers: a pilot randomized trial to modify disease expression. Use of nicorandil is associated with increased risk for gastrointestinal ulceration and perforation-a nationally representative population-based study. Evidence that ranolazine behaves as a weak beta1and beta2-adrenoceptor antagonist in the rat [correction of cat] cardiovascular system. Intervessel (arteries and veins) and heart/vessel selectivities of therapeutically used calcium entry blockers: variable, vessel-dependent indexes. Three minute, but not one minute, ischemia and nicorandil have a preconditioning effect in patients with coronary artery disease. The enigma of nitroglycerin bioactivation and nitrate tolerance: news, views and troubles. Exercise capacity after single and twice-daily doses of nicorandil in chronic stable angina pectoris. Heart disease and stroke statistics-2015 update: a report from the American Heart Association. Organic nitrates: update on mechanisms underlying vasodilation, tolerance and endothelial dysfunction. Nitrate tolerance, oxidative stress, and mitochondrial function: another worrisome chapter on the effects of organic nitrates. Attenuation of anti-ischemic efficacy during chronic therapy with nicorandil in patients with stable angina pectoris. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. Current medical therapies for patients with peripheral arterial disease: a critical review. Nitroglycerin-induced S-nitrosylation and desensitization of soluble guanylyl cyclase contribute to nitrate tolerance. Sublingual nitroglycerin delays arterial wave reflections despite increased aortic "stiffness" in patients with hypertension: a Doppler echocardiography study. Central role of mitochondrial aldehyde dehydrogenase and reactive oxygen species in nitroglycerin tolerance and crosstolerance. Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated cardiomyopathy. Treatment with the 3-ketoacyl-CoA thiolase inhibitor trimetazidine does not exacerbate whole-body insulin resistance in obese mice. Direct and indirect effects of calcium entry blocking agents on isovolumic left ventricular relaxation in conscious dogs. Elevated arterial pressure causes hypertrophy of the left ventricle and pathological changes in the vasculature. The prevalence of hypertension increases with age; for example, about 50% of people between the ages of 60 and 69 years old have hypertension, and the prevalence further increases beyond age 70. The success of hypertension treatment programs, such as one organized in a large integrated healthcare delivery system in the U. Between 2001 and 2009, this program increased the number of patients with a diagnosis of hypertension by 78%, as well as the proportion of subjects meeting target blood pressure goals from 44% to more than 84% (Jaffe et al. Hypertension is defined as a sustained increase in blood pressure of 140/90 mmHg or higher, a criterion that characterizes a group of patients whose risk of hypertension-related cardiovascular disease is high enough to merit medical attention. Actually, the risk of both fatal and nonfatal cardiovascular disease in adults is lowest with systolic blood pressures of less than 120 mmHg and diastolic blood pressures less than 80 mmHg; these risks increase incrementally as systolic and diastolic blood pressures rise. Recognition of this continuously increasing risk prevents a simple definition of hypertension (Go et al. Although many of the clinical trials classified the severity of hypertension by diastolic pressure, progressive elevations of systolic pressure are similarly predictive of adverse cardiovascular events; at every level of diastolic pressure, risks are greater with higher levels of systolic blood pressure. Indeed, in patients more than 50 years old, systolic blood pressures predict adverse outcomes better than do diastolic pressures. Pulse pressure, defined as the difference between systolic and diastolic pressure, may add additional predictive value (Pastor-Barriuso et al. This may be at least in part due to higher-than-normal pulse pressure indicating adverse remodeling of blood vessels, representing an accelerated decrease in blood vessel compliance normally associated with aging and atherosclerosis. The presence of pathological changes in certain target organs heralds a worse prognosis than the same level of blood pressure in a patient lacking these findings. For instance, retinal hemorrhages, exudates, and papilledema in the eyes indicate a far worse short-term prognosis for a given level of blood pressure. Left ventricular hypertrophy defined by electrocardiogram, or more sensitively by echocardiography or cardiac magnetic resonance imaging, is associated with a substantially worse long-term outcome that includes a higher risk of sudden cardiac death. The purpose of treating hypertension is to decrease cardiovascular risk; thus, other dietary and pharmacological interventions may be required to treat these additional risk factors. Optimal blood pressure goals for drug therapy are still debated, and current guidelines from cardiovascular societies differ slightly (James et al. Recently, a large comparative study in nondiabetics with increased cardiovascular risk was prematurely stopped because the group of patients treated with antihypertensives to a systolic blood pressure target of 120 mmHg, with an average of 2. The rate of adverse effects such as hypotension and worsening of renal function were higher in the intensified treatment group, yet this did not translate to a signal for real harm. The data will likely lead to a reexamination of current guideline-recommended blood pressure targets. Drugs lower blood pressure by actions on peripheral resistance, cardiac output, or both. Drugs may decrease the cardiac output by inhibiting myocardial contractility or by decreasing ventricular filling pressure. Reduction in ventricular filling pressure may be achieved by actions on the venous tone or on blood volume via renal effects. Drugs can decrease peripheral resistance by acting on smooth muscle to cause relaxation of resistance vessels or by interfering with the activity of systems that produce constriction of resistance vessels. In patients with isolated systolic hypertension, complex hemodynamics in a rigid arterial system contribute to increased blood pressure; drug effects may be mediated not only by changes in peripheral resistance but also via effects on large artery stiffness (Franklin, 2000). Concurrent use of drugs from different classes is a strategy for achieving effective control of blood pressure while minimizing dose-related adverse effects. It generally is not possible to predict the responses of individuals with hypertension to any specific drug.

The hypothalamic pulse generator located in the arcuate nucleus of the hypothalamus functions as a neuronal "clock" that fires at regular hourly intervals (A) spasms down there discount shallaki american express. This characteristic pattern of hormone secretions results from complex positive- and negative-feedback mechanisms (Hotchkiss and Knobil muscle relaxant for dogs buy shallaki with paypal, 1994) xiphoid spasms generic shallaki 60 caps otc. Changes in the ovarian follicle (top) and endometrium (bottom) also are illustrated schematically spasms prozac order shallaki paypal. Characteristic profiles are illustrated schematically for the follicular phase (day 9 spasms early pregnancy 60 caps shallaki with visa, inset on left) and luteal phase (day 17 spasms feel like baby kicking generic shallaki 60caps without a prescription, inset on right). Both the frequency (number of pulses per hour) and amplitude (extent of change of hormone release) of pulses vary throughout the cycle. In the absence of pregnancy, the corpus luteum ceases to function, steroid levels drop, and menstruation occurs. When steroid levels drop, the pulse generator reverts to a firing pattern characteristic of the follicular phase, the entire system then resets, and a new ovarian cycle occurs. In the luteal (or secretory) phase of the cycle, elevated progesterone limits the proliferative effect of estrogens on the endometrium by stimulating differentiation. Major effects include stimulation of epithelial secretions important for implantation of the blastocyst and the characteristic growth of the endometrial blood vessels seen at this time. Progesterone is thus important in preparation for implantation and for the changes that take place in the uterus at the implantation site. Later, the placenta becomes the major site of estrogen and progesterone synthesis. Estrogens and progesterone have important effects on the fallopian tube, myometrium, and cervix. In the fallopian tube, estrogens stimulate proliferation and differentiation, whereas progesterone inhibits these processes. Also, estrogens increase and progesterone decreases tubal muscular contractility, which affects transit time of the ovum to the uterus. Estrogens increase the amount of cervical mucus and its water content to facilitate sperm penetration of the cervix, whereas progesterone generally has opposite effects. Estrogens favor rhythmic contractions of the uterine myometrium, and progesterone diminishes contractions. These effects are physiologically important and may also play a role in the action of some contraceptives. Physiologically, these changes prepare the uterus for implantation, and the proper timing of events in these tissues is essential for pregnancy. The endometrium contains an epithelium lining the uterine cavity and an underlying stroma; the myometrium is the smooth muscle component responsible for uterine contractions. These cell layers, the fallopian tubes, cervix, and vagina display a characteristic set of responses to both estrogens and progestins. The luminal surface of the endometrium is a layer of simple columnar epithelial secretory and ciliated cells that is continuous with the openings of numerous glands that extend through the underlying stroma to the myometrial border. Fertilization normally occurs in the fallopian tubes, so ovulation, transport of the fertilized ovum through the fallopian tube, and preparation of the endometrial surface must be temporally coordinated for successful implantation. The endometrial stroma is a highly cellular connective tissue layer containing a variety of blood vessels that undergo cyclic changes associated with menstruation. The predominant cells are fibroblasts, but macrophages, lymphocytes, and other resident and migratory cell types also are present. During the follicular (or proliferative) phase of the cycle, estrogen begins the rebuilding Estrogens affect many tissues and have many metabolic actions in humans and animals. The effects of estrogens on selected aspects of mineral, lipid, carbohydrate, and protein metabolism are particularly important for understanding their pharmacological actions. Bone is continuously remodeled at sites called bone-remodeling units by the resorptive action of osteoclasts and the bone-forming action of osteoblasts (Chapter 48). Estrogens directly regulate osteoblasts and increase osteocyte survival by inhibiting apoptosis (Kousteni et al. However, a major effect of estrogens is to decrease the number and activity of osteoclasts. Much of the action of estrogens on osteoclasts appears to be mediated by altering cytokine (both paracrine and autocrine) signals from osteoblasts. Estrogens slightly elevate serum triglycerides and slightly reduce total serum cholesterol levels. Estrogens also promote endothelial cell growth while inhibiting the proliferation of vascular smooth muscle cells. Estrogens also alter bile composition by increasing cholesterol secretion and decreasing bile acid secretion. This leads to increased saturation of bile with cholesterol and appears to be the basis for increased gallstone formation in some women receiving estrogens. Estrogens alter a number of metabolic pathways that affect the clotting cascade (Mendelsohn and Karas, 1999). Thus, estrogens increase both coagulation and fibrinolytic pathways, and imbalance in these two opposing activities may cause adverse effects. Mechanism of Action 809 Estrogen Receptors Estrogens exert their effects by interaction with receptors that are members of the superfamily of nuclear receptors. There are significant differences between the two receptor isoforms in the ligand-binding domains and in both transactivation domains. The receptors appear to have different biological functions and respond differently to various estrogenic compounds (Kuiper et al. Estrogen receptor is expressed most abundantly in the female reproductive tract-especially the uterus, vagina, and ovaries-as well as in the mammary gland, the hypothalamus, endothelial cells, and vascular smooth muscle. Given the lipophilic nature of estrogens, absorption generally is good with the appropriate preparation. Aqueous or oil-based esters of estradiol are available for intramuscular injection, ranging in frequency from every week to once per month. Conjugated estrogens are available for intravenous or intramuscular administration. Transdermal patches that are changed once or twice weekly deliver estradiol continuously through the skin. Preparations are available for topical use in the vagina or for application to the skin. For many therapeutic uses, estrogen preparations are available in combination with a progestin. All estrogens are labeled with precautionary statements urging the prescribing of the lowest effective dose and for the shortest duration consistent with the treatment goals and risks for each individual patient. This remodeling facilitates the exchange of the recruited proteins such that other coactivators. The micronized formulations yield a large surface for rapid absorption to partially overcome low absolute oral bioavailability due to first-pass metabolism (Fotherby, 1996). Addition of the ethinyl substituent at C17 (ethinyl estradiol) inhibits first-pass hepatic metabolism. Other common oral preparations contain conjugated equine estrogens, which are primarily the sulfate esters of estrone, equilin, and other naturally occurring compounds; esterified esters; or mixtures of synthetic conjugated estrogens prepared from plant-derived sources. These are hydrolyzed by enzymes present in the lower gut that remove the charged sulfate groups and allow absorption of estrogen across the intestinal epithelium. In another oral preparation, estropipate, estrone is solubilized as the sulfate and stabilized with piperazine. Due largely to differences in metabolism, the potencies of various oral preparations differ widely; ethinyl estradiol, for example, is much more potent than conjugated estrogens. A number of foodstuffs and plant-derived products, largely from soy, are available as nonprescription items and often are touted as providing benefits similar to those from compounds with established estrogenic activity. In theory, these preparations could produce appreciable estrogenic effects, but their efficacy at relevant doses has not been established in human trials (Fitzpatrick, 2003). Administration of estradiol via transdermal patches provides slow, sustained release of the hormone, systemic distribution, and more constant blood levels than oral dosing. Estradiol is also available as a topical emulsion applied to the upper thigh and calf or as a gel applied once daily to the arm. The transdermal route does not lead to the high levels of the drug that occur in the portal circulation after oral administration, and it is thus expected to minimize hepatic effects of estrogens. Preparations available for intramuscular injection include compounds such as estradiol valerate or estradiol cypionate and may be absorbed over several weeks following a single intramuscular injection. Preparations of estradiol and conjugated estrogen creams are available for topical administration to the vagina. These are effective locally, but systemic effects also are possible due to significant absorption. A 3-month vaginal ring may be used for slow release of estradiol, and tablets are also available for vaginal use (Vagifem). Estradiol, ethinyl estradiol, and other estrogens are extensively bound to plasma proteins. Due to their size and lipophilic nature, unbound estrogens distribute rapidly and extensively. Variations in estradiol metabolism occur and depend on the stage of the menstrual cycle, menopausal status, and several genetic polymorphisms (Herrington and Klein, 2001). In general, the hormone undergoes rapid hepatic biotransformation, with a plasma t1/2 measured in minutes. Estradiol is converted primarily by 17-hydroxysteroid dehydrogenase to estrone, which undergoes conversion by 16-hydroxylation and 17-keto reduction to estriol, the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via (1) sulfate and glucuronide conjugation in the liver, (2) biliary secretion of the conjugates into the intestine, and (3) hydrolysis in the gut (largely by bacterial enzymes) followed by reabsorption. Ethinyl estradiol is cleared much more slowly than estradiol due to decreased hepatic metabolism, and the elimination-phase t1/2 in various studies ranges from 13 to 27 h. Unlike estradiol, the primary route of biotransformation of ethinyl estradiol is via 2-hydroxylation and subsequent formation of the corresponding 2- and 3-methyl ethers. Mestranol, another semisynthetic estrogen and a component of some combination oral contraceptives, is the 3-methyl ether of ethinyl estradiol. In the body, it undergoes rapid hepatic demethylation to ethinyl estradiol, which is its active form (Fotherby, 1996). In general, the trans conformations have antiestrogenic activity, whereas the cis conformations display estrogenic activity. However, the pharmacological activity of the trans compound depends on the species, target tissue, and gene. Toremifene is a triphenylethylene with a chlorine substitution at the R2 position. Raloxifene is a polyhydroxylated nonsteroidal compound with a benzothiophene core. Clomiphene citrate is a triphenylethylene; its two isomers, zuclomiphene (cis clomiphene) and enclomiphene (trans clomiphene), are a weak estrogen agonist and a potent antagonist, respectively. The pharmacological goal of these drugs is to produce beneficial estrogenic actions in certain tissues. Tamoxifen and toremifene are used for the treatment of breast cancer, and raloxifene is used primarily for the prevention and treatment of osteoporosis and to reduce the risk of invasive breast cancer in high-risk postmenopausal women. Clomiphene is approved for the treatment of infertility in anovulatory women, and fulvestrant is used for the treatment of breast cancer in women with disease progression after tamoxifen. Tamoxifen exhibits antiestrogenic, estrogenic, or mixed activity depending on the species and target gene measured. For example, tamoxifen inhibits the proliferation of cultured human breast cancer cells and reduces tumor size and number in women (Jaiyesimi et al. Tamoxifen treatment causes a 2- to 3-fold increase in the relative risk of deep vein thrombosis and pulmonary embolism and a roughly 2-fold increase in endometrial carcinoma (Smith, 2003). Tamoxifen produces hot flashes and other adverse effects, including cataracts and nausea. Due to its agonist activity in bone, it does not increase the incidence of fractures when used in this setting. Raloxifene is an estrogen agonist in bone, where it exerts an antiresorptive effect. Adverse effects include hot flashes and leg cramps and a 3-fold increase in deep vein thrombosis and pulmonary embolism (Cummings et al. Raloxifene acts as a partial agonist in bone but does not stimulate endometrial proliferation in postmenopausal women. In humans and other species, 4-hydroxytamoxifen is produced via hepatic metabolism, and this compound is considerably more potent than the parent drug as an antiestrogen. The major route of elimination from the body involves N-demethylation and deamination. The drug undergoes enterohepatic circulation, and excretion is primarily in the feces as conjugates of the deaminated metabolite. Polymorphisms affect the rate of tamoxifen metabolism to its more potent 4-hydroxy metabolite and may affect its therapeutic activity in breast cancer (Chapter 67).

Currently muscle relaxant education order shallaki cheap online, effort is under way for development of gas-releasing molecules that could deliver H2S and other therapeutic gases to diseased tissue muscle relaxant zanaflex generic shallaki 60 caps with mastercard. Brain surface protrusion during enflurane zanaflex muscle relaxant 60 caps shallaki with visa, halothane kidney spasms after stent removal buy discount shallaki line, and isoflurane anesthesia in cats muscle relaxant zanaflex cheap shallaki. General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal quetiapine muscle relaxer cheap shallaki 60caps. Prolonged exposure to inhalational anesthetic nitrous oxide kills neurons in adult rat brain. Peri-operative anaesthetic myocardial preconditioning and protection-cellular mechanisms and clinical relevance in cardiac anaesthesia. A new gaseous signaling molecule emerges: cardioprotective role of hydrogen sulfide. Inorganic fluoride nephrotoxicity: prolonged enflurane and halothane anesthesia in volunteers. Update on neonatal anesthetic neurotoxicity: insight into molecular mechanisms and relevance to humans. When applied locally to nerve tissue in appropriate concentrations, local anesthetics can act on any part of the nervous system and on every type of nerve fiber, reversibly blocking the action potentials responsible for nerve conduction. Thus, a local anesthetic in contact with a nerve trunk can cause both sensory and motor paralysis in the area innervated. These effects of clinically relevant concentrations of local anesthetics are reversible with recovery of nerve function and no evidence of damage to nerve fibers or cells in most clinical applications. History the first local anesthetic, cocaine, was serendipitously discovered to have anesthetic properties in the late 19th century. For centuries, Andean natives have chewed an alkali extract of these leaves for its stimulatory and euphoric actions. When, in 1860, Albert Niemann isolated cocaine, he tasted his newly isolated compound, noted that it numbed his tongue, and a new era began. Shortly thereafter, Halstead popularized its use in infiltration and conduction block anesthesia. Because of its toxicity and addictive properties (Chapter 24), a search for synthetic substitutes for cocaine began in 1892 with the work of Einhorn and colleagues, resulting in the synthesis of procaine, which became the prototype for local anesthetics for nearly half a century. Typical local anesthetics contain hydrophilic and hydrophobic moieties that are separated by an intermediate ester or amide linkage. A broad range of compounds containing these minimal structural features can satisfy the requirements for action as local anesthetics. The hydrophilic group usually is a tertiary amine but also may be a secondary amine; the hydrophobic moiety must be aromatic. The nature of the linking group determines some of the pharmacological properties of these agents. For example, plasma esterases readily hydrolyze local anesthetics with an ester link. The structure-activity relationship and the physicochemical properties of local anesthetics have been well reviewed (Courtney and Strichartz, 1987). Hydrophobicity increases both the potency and the duration of action of the local anesthetics; association of the drug at hydrophobic sites enhances the partitioning of the drug to its sites of action and decreases the rate of metabolism by plasma esterases and hepatic enzymes. In addition, the receptor site for these drugs on Na+ channels is thought to be hydrophobic (see Mechanism of Action), so that receptor affinity for anesthetic agents is greater for the more hydrophobic drugs. Hydrophobicity also increases toxicity, so that the therapeutic index is decreased for more hydrophobic drugs. Molecular size influences the rate of dissociation of local anesthetics from their receptor sites. This characteristic is important in rapidly firing cells, in which local anesthetics bind during action potentials and dissociate during the period of membrane repolarization. Rapid binding of local anesthetics during action potentials causes the frequency and voltage dependence of their action. Quaternary analogues of local anesthetics block conduction when applied internally to perfused giant axons of squid but are relatively ineffective when applied externally. These observations suggest that the site at which local anesthetics act, at least in their charged form, is accessible only from the inner surface of the membrane (Narahashi and Frazier, 1971; Strichartz and Ritchie, 1987). Therefore, local anesthetics applied externally first must cross the membrane before they can exert a blocking action. The Local Anesthetic Receptor Site on Na+ Channels the major mechanism of action of these drugs involves their interaction with one or more specific binding sites within the Na+ channel (Butterworth and Strichartz, 1990). The Na+-selective transmembrane pore of the channel resides in the center of a nearly symmetrical structure formed by the four homologous domains. The voltage dependence of channel opening is hypothesized to reflect conformational changes that result from the movement of "gating charges" within the voltage sensor module of the sodium channel in response to changes in the transmembrane potential. The gating charges are located in the S4 transmembrane helices, which are hydrophobic and positively charged, containing lysine or arginine residues at every third position. The transmembrane pore of the Na+ channel is surrounded by the S5 and S6 transmembrane helices and the short membrane-associated segments between them that form the P loop. Amino acid residues in these short segments are the most critical determinants of the ion conductance and selectivity of the channel. After it opens, the Na+ channel inactivates within a few milliseconds due to closure of an inactivation gate. Conduction block can be demonstrated in squid giant axons from which the axoplasm has been removed. Local anesthetics block conduction by decreasing or preventing the large transient increase in the permeability of excitable membranes to Na+ that normally is produced by a slight depolarization of the membrane (Chapters 8, 11, and 14; Strichartz and Ritchie, 1987). This action of local anesthetics is due to their direct interaction with voltage-gated Na+ channels. As the anesthetic action progressively develops in a nerve, the threshold for electrical excitability gradually increases, the rate of rise of the action potential declines, impulse conduction slows, and the safety factor for conduction decreases. These factors decrease the probability of propagation of the action potential, and nerve conduction eventually fails. Local anesthetics can bind to other membrane proteins (Butterworth and Strichartz, 1990). Most local anesthetics consist of a hydrophobic (aromatic) moiety (black), a linker region (orange), and a substituted amine (hydrophilic region, red). Procaine is a prototypic ester-type local anesthetic; esters generally are rapidly hydrolyzed by plasma esterases, contributing to the relatively short duration of action of drugs in this group. Lidocaine is a prototypic amide-type local anesthetic; these structures generally are more resistant to clearance and have longer durations of action. There are exceptions, including benzocaine (poorly water soluble; used only topically) and the structures with a ketone, an amidine, and an ether linkage. A two-dimensional representation of the (center), 1 (left), and 2 (right) subunits of the voltage-gated Na+ channel from mammalian brain. The polypeptide chains are represented by continuous lines with length approximately proportional to the actual length of each segment of the channel protein. The S4 transmembrane segments in each homologous domain of the subunit serve as voltage sensors. Electrical field (negative inside) exerts a force on these charged amino acid residues, pulling them toward the intracellular side of the membrane; depolarization allows them to move outward and initiate a conformational change that opens the pore. The S5 and S6 transmembrane segments and the short membrane-associated loop between them (P loop) form the walls of the pore in the center of an approximately symmetrical square array of the four homologous domains (see B). It is thought to fold into the intracellular mouth of the pore and occlude it within a few milliseconds after the channel opens. The four homologous domains of the Na+ channel subunit are illustrated as a square array, as viewed looking down on the membrane. The sequence of conformational changes that the Na+ channel undergoes during activation and inactivation is diagrammed. On depolarization, each of the four homologous domains sequentially undergoes a conformational change to an activated state. This loop folds over the intracellular mouth of the transmembrane pore during the process of inactivation and binds to an inactivation gate "receptor" formed by the intracellular mouth of the pore. Ancestral Na+ channels in bacteria comprise four identical subunits, each similar to one of the four domains of the mammalian Na+ channel subunit and containing a similar voltage sensor and pore-lining segment. A voltage-gated Na+ channel may be thought of as an antechamber (extracellular funnel) that feeds into a constricted area (selectivity filter), which opens onto a larger volume (central cavity) that has an exit door (gate). The effect of an action potential is to initiate a conformational change in the selectivity funnel region of the channel, moving the positive charges outward and away from the pore interior. Frequency and Voltage Dependence the degree of block produced by a given concentration of local anesthetic depends on how the nerve has been stimulated and on its resting membrane potential. Thus, a resting nerve is much less sensitive to a local anesthetic than one that is repetitively stimulated; higher frequency of stimulation and more positive membrane potential cause a greater degree of anesthetic block. These frequency- and voltage-dependent effects of local anesthetics occur because the charged form of the local anesthetic molecule gains access to its binding site within the pore primarily when the Na+ channel is open and because the local anesthetic binds more tightly to and stabilizes the inactivated state of the Na+ channel (Butterworth and Strichartz, 1990; Courtney and Strichartz, 1987; Hille, 1977). Remarkably, the conformation of the local anesthetic receptor site is changed considerably in the inactivated state (Payandeh et al. Local anesthetics exhibit frequency and voltage dependence to different extents depending on their pKa, lipid solubility, molecular size, and binding to different channel states. In general, the frequency dependence of local anesthetic action depends critically on the rate of dissociation from the receptor site in the pore of the Na+ channel. A high frequency of stimulation is required for rapidly dissociating drugs so that drug binding during the action potential exceeds drug dissociation between action potentials. Dissociation of smaller and more hydrophobic drugs is more rapid, so a higher frequency of stimulation is required to yield frequency-dependent block. Frequency-dependent block of ion channels is also important for the actions of antiarrhythmic drugs (Chapter 30). Therefore, they generally are marketed as water-soluble salts, usually hydrochlorides. Because local anesthetics are weak bases (typical pKa values range from 8 to 9), their hydrochloride salts are mildly acidic. This property increases the stability of the local anesthetic esters and the catecholamines added as vasoconstrictors. Under usual conditions of administration, the pH of the local anesthetic solution rapidly equilibrates to that of the extracellular fluids. Although the unprotonated species of the local anesthetic is necessary for diffusion across cellular membranes, it is the cationic species that interacts preferentially with Na+ channels. The results of experiments on anesthetized mammalian nonmyelinated fibers support this conclusion (Ritchie and Greengard, 1966). In these experiments, conduction could be blocked or unblocked merely by adjusting the pH of the bathing medium to 7. The primary role of the cationic form also was demonstrated by Narahashi and Frazier, who perfused the extracellular and axoplasmic surface of the giant squid axon with tertiary and quaternary amine local anesthetics and found that the quaternary amines were active only when perfused intracellularly (Narahashi and Frazier, 1971). However, the unprotonated molecular forms also possess some anesthetic activity (Butterworth and Strichartz, 1990). Classical experiments with intact nerves showed that the wave in the compound action potential, which represents slowly conducting, small-diameter myelinated fibers, was reduced more rapidly and at lower concentrations of cocaine than was the wave, which represents rapidly conducting, large-diameter fibers (Gasser and Erlanger, 1929). In general, autonomic fibers, small unmyelinated C fibers (mediating pain sensations), and small myelinated A fibers (mediating pain and temperature sensations) are blocked before the larger myelinated A, A, and A fibers (mediating postural, touch, pressure, and motor information) (Raymond and Gissen, 1987). The differential rate of block exhibited by fibers mediating different sensations is of considerable practical importance in the use of local anesthetics. The precise mechanisms responsible for this apparent specificity of local anesthetic action on pain fibers are not known, but several factors may contribute. The initial hypothesis was that sensitivity to local anesthetic block increases with decreasing fiber size, consistent with high sensitivity for pain sensation mediated by small fibers and low sensitivity for motor function mediated by large fibers (Gasser and Erlanger, 1929). However, when nerve fibers are dissected from nerves to allow direct measurement of action potential generation, no clear correlation of the concentration dependence of local anesthetic block with fiber diameter is observed (Fink and Cairns, 1984; Franz and Perry, 1974; Huang et al. Therefore, it is unlikely that the fiber size per se determines the sensitivity to local anesthetic block under steady-state conditions. Because a fixed number of nodes must be blocked to prevent conduction, small fibers with closely spaced nodes of Ranvier may be blocked more rapidly during treatment of intact nerves because the local anesthetic reaches a critical length of nerve more rapidly. Differences in tissue barriers and location of smaller C fibers and A fibers in nerves also may influence the rate of local anesthetic action. Consequently, maneuvers that keep the drug at the nerve prolong the period of anesthesia. Note, however, that epinephrine dilates skeletal muscle vascular beds via actions at 2 adrenergic receptors and therefore has the potential to increase systemic toxicity of anesthetic deposited in muscle tissue. Some of the vasoconstrictor agents may be absorbed systemically, occasionally to an extent sufficient to cause untoward reactions (see the next section). There also may be delayed wound healing, tissue edema, or necrosis after local anesthesia. These effects seem to occur partly because sympathomimetic amines increase the O2 consumption of the tissue; this, together with the vasoconstriction, leads to hypoxia and local tissue damage. Thus, the use of vasoconstrictors in local anesthetic preparations for anatomical regions with limited collateral circulation is avoided. Ventricular tachycardia and fibrillation are relatively uncommon consequences of local anesthetics other than bupivacaine. The antiarrhythmic effects of local anesthetics such as lidocaine and procainamide are discussed in Chapter 30.

On reconstitution of immune function muscle relaxant antagonist cheap shallaki generic, the recipient no longer recognizes new antigens provided during a critical period as "nonself spasms meaning in telugu generic shallaki 60 caps on line. Specific therapies are aimed at resolving acute attacks muscle relaxant skelaxin 800 mg purchase shallaki 60caps amex, reducing recurrences and exacerbations spasms and pain under right rib cage purchase shallaki american express, and slowing the progression of disability muscle relaxant injection generic shallaki 60caps with mastercard. The mAb natalizumab muscle relaxant hiccups order shallaki american express, directed against the adhesion molecule 4 integrin, antagonizes interactions with integrin heterodimers containing 4 integrin, such as 41 integrin that is expressed on the surface of activated lymphocytes and monocytes. In patients with cardiac issues-particularly with bundle branch blocks- fingolimod should be avoided. Dimethyl fumarate appears to have multiple immunomodulatory effects and is an activator of nrf2 that mediates antioxidative response. The drug seems to be safe, although gastrointestinal side effects can occasionally cause difficulties. Patients should not be required to "fail" before receiving alternative treatments. Risk of teratogenicity precludes use in women who are, or intend to become, pregnant. The factors that determine drug efficacy in any individual patient are largely undefined, and good clinical judgment is essential for treatment selection. What is not clear is whether any of these agents will prevent or diminish the later onset of secondary progressive disease, which causes more severe disability. A randomized controlled trial of corticosteroids in the treatment of acute optic neuritis. Clinical pharmacokinetics and pharmacodynamics of prednisolone and prednisone in solid organ transplantation. Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis. Kidney transplantation with minimized maintenance: alemtuzumab induction with tacrolimus monotherapy-an open label, randomized trial. Conversion from mycophenolate mofetil to entericcoated mycophenolate sodium in renal transplant recipients with gastrointestinal tract disorders. Glatiramer acetate (Copaxone) induces degenerate, Th2polarized immune responses in patients with multiple sclerosis. A network meta-analysis of the efficacy of belatacept, cyclosporine and tacrolimus for immunosuppression therapy in adult renal transplant recipients. Generic immunosuppression in solid organ transplantation: systematic review and meta-analysis. Antibody induction therapy in renal transplant patients receiving calcineurin-inhibitor immunosuppressive regimens: a comparative review. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. A retrospective analysis of 72 patients on prior efalizumab subsequent to the time of voluntary market withdrawal in 2009. Antigen presentation, autoantigens, and immune regulation in multiple sclerosis and other autoimmune diseases. T-cell co-stimulatory blockade in transplantation: two steps forward one step back! Alefacept combined with tacrolimus, mycophenolate mofetil and steroids in de novo kidney transplantation: a randomized controlled trial. Influence of induction modality on the outcome of deceased donor kidney transplant recipients discharged on steroid-free maintenance immunosuppression. The rise of civilization in conjunction with the domestication of plants and animals permitted people to live in denser communities with each other and with their animals. Such proximity provided ideal breeding grounds for infectious pathogens, and their spread resulted in epidemics throughout the world. As people began to question the underlying causes of disease and the apparent protection to reinfection afforded to some survivors of a disease, ideas of immunity and disease prevention were born, apparently as early as the 5th century. Variolation involved taking liquid from a smallpox pustule of an infected patient, cutting the skin of an uninfected person, and then introducing the inoculum. Lady Montagu, herself a survivor of smallpox, reported that certain Turkish women would open a wound in healthy individuals and introduce the contents of a smallpox vesicle with a large needle, thereby providing a level of protection against smallpox. Lady Montagu had herself and a son variolated and later had a daughter successfully variolated in London under the auspices of physicians of the Royal Society. The program met with general success but was opposed by many physicians, fearful that inoculation spread the disease and worried by deaths after inoculation (~2% of those inoculated). One Puritan religious leader, Edmund Massey, preached against inoculation, quoting from the book of Job (Job 2:7: "So Satan went forth from the presence of the Lord and smote Job with sore boils. In 1796, Edward Jenner, who coined the term vaccination, from vacca, Latin for "cow," helped to advance vaccine safety. Jenner infected a boy with cowpox pus from an infected milkmaid; the boy got mildly ill from cowpox, recovered, and when challenged with smallpox collected from scabs of a smallpox patient, was unaffected, showed no symptoms, and was fully protected against the disease. Thus, it was possible to inoculate against a disease using material from a related but less-harmful disease. By the early to mid-19th century, vaccination was accepted widely, and governments in the U. There was also a sense that immunity waned with time, and revaccinations were introduced, producing a sustained diminution of smallpox. The work of Pasteur and Koch established a link between microorganisms and disease and provided the scientific understanding to develop more specific vaccines. Preservatives (glycerol was an early additive) and refrigeration increased shelf life of vaccines and permitted their wider distribution. The cells of the immune system began to be identified around 1890, followed by the discovery of antibodies and hyperimmune serum and demonstration of the efficacy of adjuvants (aluminum was the first) to increase immunogenicity (Marrack et al. In the 1950s, freeze-drying became standard, permitting worldwide distribution of purified vaccines. One was polio, an incurable neurological disease causing muscle wasting, paralysis, and death if the diaphragm is affected. The Salk vaccine, an inactivated virus preparation administered by injection, was followed in 1961 by the Sabin oral vaccine, which employs an attenuated poliovirus that provides immunity to all three types of poliovirus. Eradication of polio depends on interruption of person-to-person transmission, which requires that a high percentage of the susceptible population be inoculated. Most adults in developed countries are immune, but when a significant fraction of children is unvaccinated, there is the potential for an outbreak because wild polioviruses circulate. These fundamental observations and experiments paved the way for the modern vaccines that have reduced mortality and morbidity rates from infectious pathogens across the globe. Modern laboratory technologies have rendered vaccines safe and highly effective against infectious pathogens and virus-transforming cancers and against neoantigens on cancerous cells. If the pathogen is not controlled, the innate immune system then recruits the humoral (antibody-secreting B cell) and cellular (T cell) arms of the adaptive immune response to specifically target and destroy the invading pathogen. For those who fall behind or start late, provide catch-up vaccination at the earliest opportunity as indicated by the green bars. These memory cells confer host protection against reinfection with the same pathogen. During a second response, memory cells use their specific antigen receptors to recognize the invading pathogen. This results in their activation and expansion to directly kill infected cells (via T cells) or generate antibodies (via B cells) that will neutralize the pathogen. As a means of generating immunological memory, uninfected individuals are given a controlled infection or exposed to antigen that elicits an immune response. When these vaccinated individuals are subsequently infected with these pathogens in their environment, the responses of their memory T and B cells outpace the invading microbes to neutralize and prevent their spread in a much more rapid and greater magnitude secondary response. B cell clonal expansion results in the differentiation of long-lived memory B cells and emergence of shorter-lived plasma cells that produce antibodies. During the primary response, following the vaccination, B cells will undergo this differentiation process and will initially secrete IgM antibodies. Days after the response is initiated, B cells will undergo clonal selection and will produce IgG, which is a higher-affinity antibody with enhanced pathogen neutralization capacity. Differentiated plasma cells can also produce other antibody classes, such as IgA, IgD, and IgE, that have unique functions. IgD can be expressed on the surface of B cells; its function continues to be investigated. Because IgG antibodies have undergone a selection process that increases their affinity, these antibody types are the targets of vaccine design. Secondary responses after vaccination therefore elicit a faster and larger B-cell response, and these B cells primarily make IgG antibodies (Clem, 2011). Unlike B cells, T cells target intracellular pathogens that have infected host cells. Like B cells, antigen-memory T cells survive long term and provide protection for future encounters with their specific antigen. Active A natural infection that stimulates the immune response in uninfected individuals may lead to development of immunological memory and protection from reinfection, as in the case of infection with the MeV. This only occurs if the individual survives the primary infection, which is not always the case for viruses like measles, influenza, or ebola. Active immunization through injection of artificial antigens elicits a controlled immune response leading to the generation of immunological memory. This type of immunization, compared to natural infection, does not cause infectious disease or compromise the life of the individual. Thus, vaccine technologies through active stimulation of the immune system ensure that the individual survives and has protection against the pathogen in the natural environment. Immunization Strategies Immunity can be achieved from either passive or active methods involving exposure to natural infection or through artificial human-made antigens. Passive Passive immunity involves the transfer of preformed antibodies from an immune individual to a nonimmune individual to confer temporary immunity. An example of passive natural immunity is the transfer of antibodies from mother to fetus during pregnancy and through breast milk and colostrum consumed by an infant. These antibodies enter the body and provide a first line of defense to the fetus or infant, which otherwise has no immunity to any pathogen. An example of artificial passive immunization is the injection of antivenom antibodies. Animals are immunized with venom antigen and their hyperimmunized serum is transfused into the patient. Antivenom can be monovalent, effective against one type of venom, or polyvalent and effective against venom from multiple species. Early administration after injury is critical because antivenom can halt but not reverse venom damage. Even though antivenom is purified, trace proteins remain, and these can trigger anaphylaxis or serum sickness in patients. Most antivenoms are administered intravenously but can also be injected intramuscularly against stonefish and redback spider venom. Antivenoms have been developed against venomous spiders, acarids, insects, scorpions, marine animals, and snakes. There are many different types of vaccines, each with advantages and disadvantages. Vaccine design involves an understanding of the nature of the microbe, the tropism of the pathogen, and the practical need in certain regions of the world. Live Attenuated Live attenuated vaccines use a weakened form of a virus that contains antigens that appropriately stimulate an immune response. Such viruses have been passaged to reduce their virulence but retain immunogenic antigens that elicit strong humoral and cellular responses and the development of memory cells after one or two doses. After several passages, the virus can no longer infect human cells but retains immunogenic capacity. These attenuated viruses can elicit a robust immune response because they are similar to the natural pathogen. Because these are live viruses, they generally must be refrigerated to retain their activity. In remote areas of the world where refrigeration is not available, obtaining and storing this type of vaccine can be limiting. Because viruses can mutate and change in the host, it may be possible that viruses can become virulent again and cause disease, although the frequency of adverse reactions using these vaccines is very low. Furthermore, attenuated vaccines cannot be utilized in immune-compromised individuals. Measles, polio, rotavirus, yellow fever, and chickenpox viruses are examples of pathogens for which live attenuated vaccines have been generated. A vaccine against Vibrio cholera has been generated this way (currently not approved in the U. Killing pathogens through the use of heat, radiation, or chemicals to inactivate them generates the antigenic starting materials. The dead pathogens can no longer replicate or mutate to their disease-causing state and thus are safe. These types of vaccines are useful because they can be freeze-dried and transported without refrigeration, an important consideration in reaching developing countries. A drawback with inactivated vaccines is that they induce an immune response that is much weaker than that induced by the natural infection; thus, patients require multiple doses to sustain immunity to the pathogen. In areas where people have limited access to healthcare, ensuring that these multiple doses are delivered on time can be problematic and may result in reduced immunity to the pathogen, as in the case of poliovirus endemic disease.

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