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Antibodies 70 discount duloxetine 60 mg fast delivery anxiety symptoms urination,000/cu mm of blood in last trimester) and resolves are demonstrated against platelet specific alloantigens 60mg duloxetine for sale anxiety medication over the counter. Though platelets are small in size 60 mg duloxetine amex anxiety symptoms after quitting smoking, they have highly developed membrane and cellular cytoskeletal system, open canalicular system, alpha and dense granules, and membrane glycoproteins. All these cellular specializations help in platelet functions: adhesion, aggregation, activation, and secretion. Primary hemostasis (temporary hemostatic plug formation) is the first and important step in hemostasis, which mainly depends on platelets. Platelet also paly role in clotting by activating few clotting factors and promoting clot retraction. Platelet count less than 50,000 per cu mm of blood is called critical count, as bleeding is significant below this count. In theory examination, “Role of platelets in hemostasis”, “Steps and regulation of thrombopoiesis”, and “Structure, properties and functions of platelets” may come as Long Questions. Temporary hemostatic plug, properties of platelets, thrombopoiesis, platelet granules, cytoskeletal and canalicular systems of platelets, functions of platelets, and platelet function tests may come as Short Questions in exams. Appreciate the physiological basis of use of fibrinolytic agents in coronary artery disease and stroke. List the investigations for detection of defects in temporary and definitive hemostatic plug formation. Later, few more were Coagulation of blood is a vital physiological process, as added to the list. Blood is maintained in a Scientist contributed fluid state in the vascular compartment, yet swiftly coagu- lates to seal a vascular injury. Failure to form clot results in In 1905, Paul Morawitz was the first scientist who systematically assembled coagulation factors into hemorrhage or thromboembolic phenomenon. Paul Morawitz hemostasis is the coagulation of blood, the process which is simultaneously activated along with the activation of Factor I platelets. It is a dimeric glycoprotein with molecular weight of present in their inactive form in plasma. The genes for three chains of fibrinogen are found in reactions involving clotting factors. It is an important physiological initiator of extrinsic pathway for blood coagulation. Fibrinogen is present in plasma and α-granules of vasation of blood from the injured vessel, circulating platelet. Fibrin forms the structural meshwork that transforms steps of intrinsic and extrinsic pathways of blood coagula- the loose platelet plug into a solid hemostatic plug. This is a large glycoprotein with molecular weight 333,000 and plasma half-life of about 12h. It is a single chain zymogen with molecular weight thrombin to thrombin, though it also participates in 72,000 and plasma half-life of about 60 h. The gene for human prothrombin is located on chro- glutamic acid residues that are important in activating mosome 11 close to the centromere. This activity is physiologically expressed on the surface of Oscar D Ratnoff and Joan E Colopy worked in the field of blood coagulation. It possesses receptor contains 731 amino acids with molecular weight of mediated proinflammatory activity. The gene for thrombomodulin is located on chromo- platelets, monocytes and macrophages. When thrombin binds with thrombomodulin, the the gene for B chain is located on chromosome 1. Thrombin causes cleavage of A and B subunits of in turn, causes 2000-fold activation of protein C. In addition to its nonenzymatic function in contact Protein S activation, it acts as a thiol protease inhibitor. It is cleaved by prekallikrein to bradykinin, a potent Protein S is a single-chain glycoprotein cofactor synthe- vasodilator. It is also synthesized by endothelial cells, megakaryocytes, Leydig cells and osteoblasts.
Lacosamide as adjunctive therapy for tory seizure clusters and status epilepticus: comparison of 200 and 400 mg loading partial-onset seizures: a randomized controlled trial duloxetine 60 mg without a prescription anxiety yelling. Lacosamide adjunctive therapy for tion in post-stroke non convulsive status epilepticus in the elderly: a proof-of-con- partial-onset seizures: a meta-analysis order duloxetine 20mg without prescription anxiety symptoms eye twitching. When clinical trials make history: demonstrating efcacy of new antie- status epilepticus: a multicenter Italian experience buy on line duloxetine relieve anxiety symptoms quickly. Conversion to lacosamide monotherapy in 72 Zaccara G, Perucca P, Loiacono G, et al. The adverse event profle of lacosamide: the treatment of focal epilepsy: results from a historical-controlled, multicenter, a systematic review and meta-analysis of randomized controlled trials. First case of lacosamide-induced years of age with refractory epilepsy: a prospective, open-label, observational, psychosis. Lacosamide as an adjunctive therapy in pediatric short-term replacement for oral lacosamide in partial-onset seizures. The following maintenance dosages are ofen used: Combination therapy without valproic acid and without enzyme-inducing agents: 100–400 mg/day (children 2–12 years of age: 1–10 mg/kg/day, maximum 300 mg/day) Initial monotherapy: 100–200 mg/day (over 12 years of age) Combination therapy with valproic acid without enzyme-inducing agents: 100–200 mg/day (children 2–12 years of age: 1–5 mg/kg/day, maximum 200 mg/day) Combination therapy with enzyme-inducing agents without valproic acid: 200–500 mg/day (children 2–12 years of age: 5–15 mg/kg/day, maximum 400 mg/day) Dosing frequency Once or twice daily, depending on expected half-life in the individual patient and type of formulation Signifcant drug Serum lamotrigine levels are reduced by enzyme-inducing antiepileptic drugs, interactions methsuximide, rifampicin, the lopinavir–ritonavir combination, combined steroid contraceptives and some other oestrogen-containing hormonal preparations. Lamotrigine may reduce the serum levels of levonorgestrel Serum level Dosage is usually individualized based on clinical response. Serum drug level monitoring monitoring is particularly useful to guide dosage adjustments in situations associated with changes in lamotrigine pharmacokinetics, such as pregnancy, puerperium and drug–drug interactions Reference range 2. Highly disadvantages variable pharmacokinetics in relation to physiological factors (e. Other action mechanisms may contribute to antiepileptic efcacy Oral bioavailability >95% Time to peak levels 1–3 h Elimination Primarily by conjugation with glucuronic acid Volume of 1. Children may have shorter half-lives Serum clearance Patients on monotherapy, patients on polytherapy receiving neither valproic acid nor enzyme-inducers, and patients receiving a combination of valproic acid and enzyme inducers: 0. Children have higher clearance values Protein binding 55% Active metabolites None Comment A very useful antiepileptic drug which can used as frst- or second-line monotherapy, or as adjunctive therapy, in the treatment of focal seizures and in some of the generalized epilepsy syndromes Introduction poorly soluble in water (0. Its extensive use has also highlighted broadly similar to that of phenytoin and carbamazepine [5,6]. The manufacturer’s product information is regu- trigine was more potent than phenytoin and carbamazepine in these larly updated, and the clinician should refer to the latest version [2,3]. A recent study using Lamotrigine produces a dose-dependent suppression of second- microdialysis in freely moving animals demonstrated that lamo- ary generalized seizures and aferdischarge duration in amygdaloid trigine blocked release of glutamate and aspartate in hippocampus and hippocampal-kindled seizures in rats (a model of complex par- of pentylenetetrazole-kindled rats . It is not readily understood tial seizures), with the efect lasting as long as 24 h in some cases why lamotrigine has a broader spectrum of clinical activity than the [8,10]. This efect was also observed in kindled rats that had previ- other sodium channel blockers, phenytoin or carbamazepine . Lamotrigine is thought to A potential explanation could be its preferential afnity for diferent produce this efect by increasing aferdischarge threshold, that is by sodium channel α subunits which have diferential regional distri- suppression of seizure initiation, not propagation. The inhibits voltage-sensitive sodium currents through a preferential pharmacokinetics of lamotrigine in adults has previously been ex- interaction with the slow inactivated sodium channel , suggest- tensively reviewed [45,46,47,48,49].. Lamotrigine does not afect normal synaptic transmis- children and adults with epilepsy [47,50]. Lamotrigine potently inhibits glu- tamate and aspartate release induced by the sodium channel opener Absorption veratrine in rat cerebral cortical slices, and displaces batrachotoxin Lamotrigine is well absorbed following oral administration and dis- from its sodium channel-binding site [19,25]. Administration of a plays an absolute bioavailability of 98% in healthy adult volunteers. A mean peak concentra- ductance involved in the release of excitatory amino acids in the tion of 1. At clinically relevant concen- adults, while afer a single oral dose of 2 mg/kg a mean peak con- trations, lamotrigine inhibits voltage-activated calcium currents in centration of 1. As the role of limbic structures in the pathophysiology of epi- Distribution leptic seizures is well established, actions of lamotrigine on these Lamotrigine is approximately 55% bound to plasma proteins in vit- structure are especially relevant. Protein binding is unafected by therapeutic concentrations of excitatory transmission in the rat amygdala by its efect on N-type phenytoin, phenobarbital and valproic acid . Renal insufciency Studies in animals show that lamotrigine is widely distributed in Twelve volunteers with chronic renal failure (mean creatinine clear- all tissues and organs, but little is known of its diferential tissue dis- ance 13 mL/min; range 6–23 mL/min) and another six individuals tribution in humans. Measurement of lamotrigine concentrations undergoing haemodialysis were each given a single 100-mg dose of in brain tissue obtained from resected brain tumours , and dur- lamotrigine .
Membrane Glycoproteins the cell membrane contains integral membrane glyco- proteins (Gp) (Fig order 60mg duloxetine otc anxiety symptoms kids. Note the presence of open Cytoskeletal system of platelets can be broadly divided canalicular system order duloxetine 40mg with mastercard symptoms 9f anxiety, dense tubular system buy 20mg duloxetine with visa anxiety uk, and alpha and dense into membrane and cytoplasmic cytoskeletal systems. When activated, they change their shape due to change in the cell membrane, which is connected to the ends of actin activity of membrane structure and cytoskeleton. This filaments that are situated close to the cell membrane and helps in release of chemicals from its granules. Filamin 1 (actin binding protein) interacts with mem- filaments and numerous granules. Frequently, they brane glycoprotein and actin present below the mem- change their shape with very long and thin processes brane. Filamin 1 also connects these proteins (mem- extending out from their body called as filopodia. Other membrane proteins include talin, vinculin, and having diameter ranging from 1. Membrane cytoskeleton plays important platelets is approximately one-third to one-fourth of red cells. Few platelets may have diameter more than half the diameter of red cells (> 4 µm). Cytoplasmic Cytoskeleton Cytoplasm contains a well-developed contractile system, Cell Membrane which consists of an extensive network of microtubules Cell membrane is covered by an exterior glycocalix coat and microfilaments. Platelets have negative charge on their surface due to There is a sub-membrane microtubular system consist- presence of sialic acid residues attached to the exte- ing of many microtubules that are arranged beneath the rior coat. The cell membrane is a trilaminar unit consisting of also associated with microtubules. Microtubules provide stability to the membrane and lipids, and glycoproteins are embedded. Thus, open canalicular system enhances the degree and rate of platelet release (see below). Platelet microfilaments consist mainly of actin molecules that polymerize into microfilamentous bundles. There are Dense Tubular System also few myosin filaments attached to actin filaments. Actin and myosin filaments constitute contractile sys- plasmic reticulum that are less extensive than canalicular tem in platelets. They form the major contractile system of the cell that binding protein that helps in calcium accumulation. Release of calcium from dense tubular system facili- their granular content to the exterior through canali- tates platelet release. Cytoplasmic Organelles Cellular Systems Cytoplasmic matrix contains microfilaments, structured filaments, and microtubules. Interspersed in the matrix There are two developed cellular systems in platelets that are various types of granules and electron dense bodies. Open Canalicular System Platelet Granules There are many canaliculi in the platelets that open to the Platelet contains numerous peroxisomes, mitochondria, exterior. The open canaliculi are extensive invaginations of cell discharge of content of granules that facilitate the process membrane deep into the cytoplasm that form the con- of hemostasis. The granules of platelets are of two types: duits for discharge of contents of granules. Presence of numerous canaliculi in platelet eliminates Alpha granules: the alpha granules are abundant in the dependence of the cell for its chemical release platelets. They contain various for their fusion with cell membrane for exocytosis, as chemicals (Table 20. They have brane facilitates the process of release of chemicals diameter of about 20–30 nm. The activated platelets change their shape and discharge their granular contents (Fig. The dis- Platelets easily adhere to the damaged vascular endothe- charge of the granular content to the exterior through lium. Platelets have the tendency to stick to the exposed collagen of the injured open canalicular system is called platelet release (see vessel wall.
Drug Interactions Tricyclic antidepressants potentiate the effects of epinephrine purchase duloxetine on line amex anxiety symptoms list. These agents order 30mg duloxetine visa anxiety 54321, however buy discount duloxetine 20mg line anxiety depression, produce several undesirable effects, including an increase in heart rate and myocardial oxygen consumption and an increase in systemic vascular resistance. Unlike the catecholamines, milrinone produces a positive inotropic effect with concurrent vasodilation and little chronotropic effect. As a result of these differences, milrinone has become a valuable tool in the treatment of children following cardiac surgery and in the management of shock. Mechanism of Action Milrinone, like its predecessor inamrinone (formerly called amrinone), is a bipyridine inotrope and vasodilator. Milrinone exhibits a concentration-dependent response, with optimal effects occurring between 100 and 300 ng/ml. In addition it has been postulated that a portion of milrinone’s action is mediated via inhibition of guanine nucleotide binding protein.. It decreases pulmonary vascular resistance in children with intracardiac left to right shunts. Therapeutic Use Use after Cardiac Surgery Several investigators have studied the effects of milrinone in reversing the low cardiac output frequently observed in infants and children after cardiac surgery. Administration of milrinone has been shown to produce a significant increase in cardiac index, with a decrease in mean atrial pressure. Although the data available to date have been promising, questions about the optimal timing for initiation of therapy, dosing, and monitoring remain. A prospective multicenter, randomized, double-blind, placebo-controlled study is currently under development to address these questions. Use in Septic Shock In addition to its use after cardiac surgery, milrinone may also be beneficial in the management of low cardiac output resulting from septic shock. In a prospective, double blind trial,36 milrinone significantly increased cardiac index, stroke volume index and oxygen delivery while decreasing systemic vascular resistance, pulmonary vascular resistance, and mean pulmonary artery pressure. No significant changes were noted in heart rate, systolic or diastolic blood pressure, mean systemic arterial pressure, or pulmonary capillary wedge pressure. It is approximately 70% bound to plasma proteins at plasma concentration of 70-400 ng/ml. The major urinary excretion products in man are milrinone (83%) and its O- glucuronide metabolite (12%). Elimination in normal subjects via the urine is rapid, with approximately 60% recovered within the first 2 hours following dosing, and approximately 90% recovered within the first 8 hours following dosing. In infants and young children undergoing cardiac surgery, the weight adjusted clearance of milrinone increases with age, ranging from 2. It is diluted to a maximum concentration of 200 mcg/ml in either saline or 5% dextrose for administration. During therapy with milrinone, blood pressure and heart rate should be monitored and rate of infusion slowed or stopped in patients showing hypotension. Fluid and electrolyte changes and renal function should be carefully monitored during therapy with milrinone. Milrinone therapy is usually initiated with a loading dose followed by a continuous infusion. Dose A loading dose of 50 mcg (10 microgram/kg as e general guideline) is used in children35 followed by maintenance infusion rates of 0. Adverse Effects As with other positive inotropes, the phosphodiesterase inhibitors have the potential to produce arrhythmias. Milrinone produces a slight shortening of atrioventricular node conduction time, which may result in an increased ventricular response rate in patients with atrial flutter or fibrillation. Other adverse effects associated with milrinone use in adult clinical trials include: hypotension (2. The incidence of thrombocytopenia is substantially less than that seen with in amrinone (2. Although pediatric studies are limited, the side effect profile of milrinone in children appears to be similar to adults. Milrinone should not be used in lieu of surgical relief of the obstruction in patients with severe obstructive aortic or pulmonic valvular disease. Like other inotropic agents, it may aggravate outflow tract obstruction in hypertrophic subaortic stenosis.