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By Z. Kalesch. North Georgia College and State University, the Military College of Georgia.

Philadelphia: Wolters Kluwer/Lippincott Williams & patients with generalized epilepsy buy 10 mg aricept. Phenobarbital and other barbiturates: methylphenobarbi- patients with temporal lobe epilepsy: a case–control study order 10mg aricept with visa. Phenobarbital for the treatment of epilepsy in the 21st century: bital pharmacokinetics during monotherapy generic 10mg aricept overnight delivery. The anticonvulsant efects of phenobarbital aricept 5mg with visa, di- nobarbitone: pharmacokinetics in Japanese patients with epilepsy – analysis by phenylhydantoin and two benzodiazepines in the baboon, Papio papio. J cokinetics of phenytoin and phenobarbital in Japanese epileptic patients using Neural Transm 1992; 35: 7–19. Pharmacol Rev P450 2C9 and 2C19 polymorphisms on phenobarbital clearance in Japanese. Curr Treat Options Neurol renal replacement therapy: a case report and pharmacokinetic analysis. Interet du dosage des anti- a prospective comparison of diazepam and phenytoin versus phenobarbital and convulsants dans le traitement des epilepsies. Intravenous phenytoin and phenobarbital: anticonvul- to phenobarbital and diphenylhydantoin serum and cerebrospinal fuid levels in sant action, brain content, and plasma binding in the rat. A comparison of four treatments diphenylhydantoin and primidone levels in epileptic patients. The relative efectiveness of fve antiepileptic drugs in plasma concentrations of phenytoin, phenobarbital and carbamazepine. Arch Neu- treatment of benzodiazepine-resistant convulsive status epilepticus: a meta-anal- rol 1986; 43: 263–265. Successful prophylaxis of febrile convul- toin monotherapy for partial onset seizures and generalised onset tonic-clonic sions with phenobarbital. Psychology, pharmacotherapy and new diagnostic ap- newly diagnosed childhood epilepsy. Cognitive and mood efects of phenobarbital intelligence and on seizure recurrence. Carbamazepine versus phenobarbital for partial onset sei- outcomes afer exposure to phenobarbital and levetiracetam for the treatment of zures in children. Phenobarbital-induced atypical absence bility of phenobarbital for childhood epilepsy in rural India. Lancet 1998; 351: seizure in benign childhood epilepsy with centrotemporal spikes. Efects of epilepsy treatments on sleep architecture and day- evidence-based analysis of antiepileptic drug efcacy and efectiveness as initial time sleepiness: an evidence-based review of objective sleep metrics. Side efects of phenobarbital and carbamaz- of antiepileptic drug efcacy and efectiveness as initial monotherapy for epilep- epine in childhood epilepsy: randomised controlled trial. Epilepsy control with phenobarbital or study of human teratogenesis associated with maternal epilepsy. Congenital malformations due to antie- and monitoring of epileptic patients in rural Mali. Efcacy assessment of phenobarbital in epilepsy: pendent risk of malformations with antiepileptic drugs: an analysis of data from a large community-based intervention trial in rural China. Metabolic disposition of primidone and tranquillizers in Ontario: a 10-year survey. Conventional haemodialysis signifcantly lowers toxic levels in patients under long-term treatment. Antiepileptic drugs interact with lite phenobarbital: efect of age and associated therapy. Stevens–Johnson syndrome in chil- of primidone during pregnancy and in the ofspring of epileptic women. Phenobarbital-associated bone marrow apla- afer administration of the acid and the propylhexedrine salt (barbexaclone). Eadie University of Queensland, Brisbane, Australia Primary indications First-line or adjunctive therapy for focal and generalized seizures (except H O for myoclonic and absence seizures) and second-line therapy for convulsive N status epilepticus Usual preparations Capsules and tablets: 25, 30, 50, 100, 200 mg O N Chewtabs: 50 mg Liquid suspension: 30 mg/5 mL, 100 mg/5 mL H Injection: 250 mg/5 mL Usual dosages Orally: 5 mg/kg/day (adults), 10 mg/kg/day (children); lower or higher maintenance doses may be needed, guided by serum level monitoring and clinical response Dosing frequency 1–2 times/day Signifcant drug Phenytoin is an enzyme-inducer and may reduce the serum levels and interactions clinical efect of many other drugs. Numerous drugs may interfere with phenytoin absorption, plasma protein binding and metabolic elimination Serum level monitoring Useful Target range Total serum concentration: 10–20 mg/L (40–80 µmol/L) Unbound serum concentration: 1–2 mg/L (4–8 µmol/L) Common/important Ataxia, dizziness, lethargy, sedation, headache, cognitive dysfunction, side-effects dyskinesia, acute encephalopathy, cutaneous and systemic hypersensitivity reactions (including fever, lymphadenopathy, liver toxicity, blood dyscrasias, vasculitis), gingival hyperplasia, folate defciency, megaloblastic anaemia, vitamin K defciency, decreased immunoglobulins, mood changes, depression, coarsened facies, hirsutism, acne, peripheral neuropathy, osteomalacia, hypocalcaemia, hormonal dysfunction, loss of libido, connective tissue alterations, pseudolymphoma, myopathy, teratogenic efects Main advantages Highly efective and inexpensive Main disadvantages Central nervous system and systemic adverse efects; non-linear elimination kinetics Mechanisms of action Blockade of neuronal voltage-dependent sodium channels Oral bioavailability 95% Time to peak levels 4–12 h Elimination Hepatic oxidation to hydroxy derivatives, then conjugation Volume of distribution 0. The molecule was synthesized in the Phenytoin prevents or reduces the severity of induced seizures early twentieth century but being less sedative than the bromides in various animal models of generalized convulsive epileptic sei- and phenobarbital, was not considered for an antiepileptic role until zures (notably in the maximal electroshock model). It is also efec- Putnam and Merritt, in the late 1930s, sought from various chem- tive in models of focal epileptic seizures, for instance electrically ical suppliers substances with molecular structural resemblances or chemically induced kindled focal seizures in rats [4]. It atively inefective against generalized seizures induced by system- was then thought an aromatic ring substituent probably enhanced ically administered chemical convulsants and also in what were any antiepileptic properties present in members of a family of mol- previously considered animal models of absence seizures (e. The substances sup- pentylenetetrazole-induced seizures) but which are now probably plied were tested in an animal model of convulsive epileptic seizures better regarded as models of myoclonic seizures. The drug is also where phenytoin proved to combine antiseizure efcacy with a rel- inefective in more recently developed and more realistic animal ative lack of sedation. Several accounts of the discovery of long the inactivation state, particularly the fast inactivated state [5], phenytoin are available [1,3]. This efect is greater when the cell membrane has been depolarized Chemistry and is in its inactive state than when it is hyperpolarized [8]. With Phenytoin (5,5′-diphenylhydantoin) is supplied for therapeutic use repeated depolarizations, the ion channel block becomes use-de- as the free acid (molecular weight 252. Phenytoin binds to the same site in the inner pore of the um salt (molecular weight 274. It is a white crystalline, relatively sodium channel as carbamazepine and lamotrigine [9]. The sodium salt of voltage- and frequency-dependent sodium channels makes part- is more water-soluble than the free acid, and is usually supplied in ly depolarized axons less capable of transmitting rapid trains of ac- capsules or as a parenteral injection (pH ~12). The corresponding tion potentials (as occur in epileptic discharges), but interferes less free acid is available in tablets or as an oral suspension. The drug has no efect on T-type calcium channels in or spectrophotometric but currently, phenytoin concentrations the thalamus important in the genesis of absence seizures [10]. High performance-liquid chromatographic-mass contributes to its antiepileptic efects is unclear. It has no efect at spectrometric methods appear to be increasingly used for research inhibitory glycine receptors [12]. Phenytoin also is a weak dopa- studies because of their sensitivity and specifcity. In the brain, in experimental preparations, for example preventing post-tetanic phenytoin achieves a slightly higher concentration than in serum. Phenytoin is transported out of the brain by a P-glycoprotein mechanism in the blood–brain barrier. Animal models suggests that if this extrusion mechanism Pharmacokinetics is well developed, or becomes induced following repeated seizures, In recent years, little has been added to the knowledge of the phar- phenytoin concentrations in the brain are disproportionately low macokinetics of phenytoin [14,15,16]. In the following account, ref- compared with simultaneous plasma water drug concentrations, erences are cited mainly for more recently established facts. Tere is some evidence that this efect occurs in humans but the signifcance is not yet clear [25]. Absorption In whole blood, the phenytoin concentration in red cells is lower The absorption rate of phenytoin from diferent oral preparations than in serum. Terefore, whole blood phenytoin concentrations may vary, but absorption is not afected by food intake. The oral are lower than simultaneously measured serum (or plasma) phe- bioavailability of phenytoin was reviewed in some detail by Neuvo- nytoin concentrations. The importance of formulation was demonstrated nearly to plasma proteins, mainly albumin. The unbound fraction of the 50 years ago when the oral bioavailability of phenytoin in the mar- drug in plasma is higher in the neonate than in the adult, and in- ket leader’s capsule formulation in Australasia was compromised creases a little with advanced age, in late pregnancy, and in the because of an interaction between the drug and the excipient cal- presence of hypoalbuminaemia (as occurs in malnutrition, liver cium sulfate. In this formulation, phenytoin has a consistent and of glycated albumin, as in diabetics. Phenytoin concentrations in complete, or nearly complete (~95%), oral bioavailability. Nonethe- cerebrospinal fuid and routinely collected saliva, tears and sweat less, there are still reports of generic phenytoin tablets whose oral are very similar to the unbound phenytoin concentrations in plas- bioavailabilities appear incomplete and, to an extent, inconsistent, ma. However, the saliva phenytoin concentration varies with saliva and whose use may be associated with breakthrough seizures [18]. Certain acidic drugs, for example Storage of phenytoin capsules under conditions of high tempera- salicylates, valproic acid and various endogenous substances (fatty ture and humidity may reduce the oral bioavailability of the drug. Such displacements are rarely important clinically, istered phenytoin was impaired during pregnancy, but subsequent but they must be kept in mind when total serum phenytoin con- studies showed that this was not so [19].

When purifed discount aricept 5mg otc, B cell preparations and specifc tor to target cell ratios can be employed for quantifcation discount 5mg aricept with amex. Each of these lymphoid cells has the (effector) lymphocytes are cytotoxic for donor (target) lym- ability to respond by proliferating following stimulation by phocytes after the two are combined in culture (Figure 28 generic aricept 5 mg. In the one-way reaction buy 10mg aricept free shipping, the donor Target cells are labeled by incubation with 51Cr at 37°C for cells are treated with mitomycin or irradiation to render them 60 min. Thus, the donor antigens stimulate tissue culture, the release of 51Cr from target cells injured by the untreated responder cells. The mixed-lymphocyte reaction usually Syringe measures a proliferative response and not an effector-cell- Nylon wool killing response. The test is important in bone marrow and organ transplantation to evaluate the degree of histoincom- patibility between donor and recipient. The transformed cell increases in size and amount of T and B lymphocytes cytoplasm. Nucleoli develop in the nucleus, which becomes (T cells pass through) lighter staining as the cell becomes a blast. The lymphocyte transformation include immunoglobulins, cytokines, and growth factors. Antiimmunoglobulin, bacterial lypopolysaccharides, and staphycoccal protein A activate B lymphocytes. The lymphocyte transformation assay is a broadly used in vitro test to evaluate lymphocyte function in patients. Strain A Strain B the lymphocyte antigen stimulation test is an assay for the in vitro assessment of impaired cell-mediated immu- nity. This test is useful to evaluate patients with genetic or Responder Stimulator acquired immunodefciencies, bacterial and viral infections, lymphocytes lymphocytes from cancer, autoimmune disorders, transplantation-related dis- from the spleen the spleen treat with X-rays or mitomycin C orders, antisperm antbodies, or previous exposure to a vari- ety of antigens, allergens, pathogens, and metals/chemicals. Lymphocytes from an animal or human sensitized used for the in vitro assessment of cell-mediated immunity to the antigen release a lymphokine called migration inhibi- in patients with immunodefciency, autoimmunity, infec- tory factor that will block migration of macrophages from tious diseases, cancer, and chemical-induced hypersensitiv- the end of the tube where the cells form an aggregated mass. Lymphocytes respond to these mitogens that stimulate large numbers of lymphocytes, without prior sen- Macrophage functional assays are tests of macrophage sitization. Mitogens may stimulate both B and T cells, of a Boyden chamber and a chemoattractant is added to the and the inability of lymphocytes to respond to mitogens sug- other end. Macrophage migration toward the chemoattrac- gests impaired cell-mediated or humoral immunity. Lymphocytes derived from nonreactive indi- viduals do not show signifcant lymphocyte toxicity. The soluble yellow dye, nitroblue tetra- zolium, is taken up by neutrophils and monocytes during phagocytosis. Neutrophils from patients with chronic granulomatous disease are unable to reduce the nitroblue tetrazolium. Sample cells fow sin- technique and provides the capability for performing many of gle fle past a narrowly focused excitation light beam that is these assays simultaneously. As the cells pass the focused excitation light beam, each cell scatters light and the neutrophil microbicidal assay is a test that assesses the may emit fuorescent light, depending on whether or not it is capacity of polymorphonuclear neutrophil leukocytes to kill labeled with a fuorochrome or is autofuorescent. The fuorescent emissions Bright is an adjective used in fow cytometry to indicate the of the cell are measured in the perpendicular directions by relative fuorescence intensity of cells being analyzed, with a photosensitive detector. Measurements of light scatter and bright designating the greatest intensity and dim representing fuorescent emission intensities are used to characterize each the lowest intensity of fuorescence. Three-color fow cytometry of cells attributable to bound fuorescent antibodies, as indi- is used to analyze blood cells by size, cytoplasmic granular- vidual cells fow in a stream past photodetectors. Immunological Methods and Molecular Techniques 851 luminol (5-amino-2,3-dihydro-1,4-phthalazinedione). This consists of a chamber Time ® Orange separated into two compartments by a Millipore flter of appropriate porosity, through which cells can migrate actively Time Red but not drop passively. The chamber is incubated sure multiple characteristics of a single cell simultaneously. These in air at 37°C for 3 h, after which the flter is removed and objective measurements are made one cell at a time, at routine rates of 500 to 4000 particles per second in a moving fuid stream. Use of three-color fow cytometry to analyze blood cells by size, cytoplasmic granu- Phycoerythrin is an extensively used label for immunofuo- larity, and surface markers labeled with different fuorochromes. This light-gathering plant protein absorbs light eff- ciently and emits a brilliant red fuorescence. A cell passing through a laser beam length (color) and intensity to a specifc collection tube. Fluorochrome staining of cells permits absorbed light to be emitted as fuorescence. Dim is an adjective used in fow cytometry to indicate the Forward angle light scatter permits identifcation of a cell in relative fuorescence intensity of cells being analyzed, with fow and determination of its size. If higher-angle light scat- dim representing the lowest intensity and bright designating ter is added, some specifc cell populations may also be iden- the greatest intensity of fuorescence. Light scatter measured at 90° to the laser beam and fow stream yields data on cell granularity or fne structure. Immunophenotyping is the use of monoclonal antibodies Light scatter depends on such factors as cell size and shape, and fow cytometry to reveal cell surface or cytoplasmic anti- cell orientation in fow, cellular internal structure, laser beam gens that yield information that may refect clonality and cell shape and wavelength, and the angle of light collection. This type of data is valuable clinically in aiding the diagnosis of leukemias and lymphomas through the use of a battery of B cell, T cell, and myeloid markers. Right angle light detector However, immunophenotyping results must be used only in α cell complexity conjunction with morphologic criteria when reaching a diag- nosis of leukemia or lymphoma. It is often used as a second label in fuorescence antibody Light Forward light detector techniques where fuorescein, an apple-green label, is also used. Chemiluminescence is the conversion of chemical energy into light by an oxidation reaction. A high-energy peroxide Forward scatter—diffracted light intermediate, such as luminol, is produced by the reaction Related to cell surface area of a precursor substance exposed to peroxide and alkali. Detected along axis of incident light in the forward direction the emission of light energy by a chemical reaction may Side scatter—reflected and refracted light occur during reduction of an unstable intermediate to a Related to cell granularity and complexity stable form. The apportion- Neutrophils ment of cells by this method follows the Poissonian dis- 600 tribution, which yields 37% of aliquots without any cells and 63% with one or more cells. This technique can be 400 used to estimate a certain cell’s frequency in a popula- Monocytes tion. For example, it may be employed to approximate the 200 frequency of helper T lymphocytes, cytotoxic T lympho- Lymphocytes cytes, or B lymphocytes in a lymphoid cell suspension or 0 to isolate cells for cloning in the production of monoclonal 0 200 400 600 800 1000 Forward Light Scatter antibodies. A small square of cotton, linen, or paper 600 impregnated with the suspected allergen is applied to the skin for 24 to 48 h. The development of red- ness (erythema), edema, and formation of vesicles constitutes 200 a positive test. The impregnation of tuberculin into a patch was used by Vollmer for a modifed tuberculin test. There 0 are multiple chemicals, toxins, and other allergens that may 400 450 500 550 600 650 700 Wavelength (nm) induce allergic contact dermatitis in exposed members of the population. The peak absorption is around 488 A skin test is any one of several assays in which a test sub- nm and the peak emission is around 530 nm. Skin tests have long been used to determine host hypersensitivity or immunity to a particular antigen or product of a microorganism. Examples include the 104 tuberculin test, the Schick test, the Dick test, the patch test, the scratch test, etc. A minute quantity of diluted erythrogenic toxin is inoculated 101 intradermally in the individual to be tested. The tuberculin test refers to the 24- to 48-h response to intradermal injection of tuberculin. A positive skin test implies an earlier induration within 24 to 48 h in positive individuals. Its prepa- ration parallels the extraction of old tuberculin or purifed Stormont test: A double intradermal tuberculin test. The tine test is a human tuberculin test that involves the Brucellin is a substance similar to tuberculin, but derived intradermal inoculation of dried, old tuberculin using a four- from a culture fltrate of Brucella abortus that is used to test pointed applicator that introduces the test substance 2 mm for the presence of delayed-type hypersensitivity to brucella below the surface. The Vollmer test (historical) is a tuberculin patch test the Schick test is a test for susceptibility to diphtheria. Development of redness and induration is used in a skin test for cell-mediated immunity against the within 24 to 36 h after administration constitutes a positive microorganism in a manner analogous to the tuberculin skin test if it persists for 4 d or longer. Neither redness nor capsulatum that is injected intradermally, in the same manner induration appears if the test is negative.

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Bronchial asthma is precipitated or induced by hista­ action of enzyme tryptophan hydroxylase 5 mg aricept sale. Histamine is released from mast cells in response to (serotonin) catalyzed by the enzyme 5­hydroxytryptophan the antibody IgE (the reagin antibody) aricept 5 mg sale. Serotonin Receptors Experimentally cheap aricept 5mg with visa, when histamine is injected into the skin generic aricept 10 mg otc, it produces sever itch. Itching associated with skin allergy Till date, seven types of serotonin receptors have been (urticaria) is cured by antihistaminics. Inhibits transmission of pain impulses in dorsal horn of spinal cord, and thus, it is an important component of endogenous analgesia system. Regulates circadian rhythm (suprachiasmatic nucleus receives heavy serotonergic innervation). Anti­ depressant drugs such as fluoxetine act by inhibiting serotonin reuptake in the brain. It inhibits feed­ ing by acting on hypothalamic and other feeding areas in the brain. Physiological Actions Clinical Correlation Serotonin mainly acts on cardiovascular system, respira­ tory system, kidney, smooth muscle, and nervous system. It produces vasodilation and increases local blood and temporarily stops urination. Central Nervous System It is released as a neurotransmitter in different parts of Clinical Importance the brain. The most important serotonergic pathway in the brain is the raphespinal system that on stimulation Bradykinin is secreted from abnormal endocrine tumors produces analgesia. It was named prostaglandin for its enumeration in the secre­ tion from prostate gland. Afterwards, prostaglandins were found to be synthesized in various tissues of the body. Scientist contributed Ulf Svante von Euler (1905-1983) was a Swedish physiologist and pharmacologist. He shared the Nobel Prize in Physiology or Medicine in 1970 for his work on neurotransmitters. His short stay as a postdoctoral student in Dale’s laboratory was very fruitful, where in 1931 he worked with John H Gaddum and discovered substance P. After return ing to Stockholm, he pursued his research, and discovered Ulf S von Euler (1905–1983) four other important endogenous active substances, prostaglandins, vesiglandin (1935), piperidine (1942) and noradre­ naline (1946). Prostaglandins increase in uterine fluid and cause enzyme phospholipase A2: necrosis of blood vessels of the uterus just before the 1. Arachidonic acid is then converted to cyclic endoper­ bleeding starts during menstrual cycle. The balance between the prostacyclin and thrombox­ Physiological Actions ane A2 determines the degree of platelet plug forma­ Prostaglandins are present in almost all the tissues of the tion (refer to Fig. Thus, prostaglandins greatly influence temporary of various organ systems, hemostasis, and metabolisms hemostasis. The con­ Prostaglandins E and F inhibit absorption of sodium and 2α centration of this chemical increases in the maternal water: Chapter 64: Local Hormones 573 1. The watery diarrhea produced in cholera is mediated in the peritubular capillary bed of kidney. Steroidal anti-inflammatory drugs such as cortisol kidney tubule to inhibit sodium reabsorption. It causes vasodilation, leading to decrease in blood as ibuprofen inhibit prostaglandin synthesis by inhibit­ pressure. It also increases capillary permeability that causes extravasation of fluid into interstitial tissue space. These episodic attacks occur due to secretion of vari­ is more in children and less in adults. Therefore, the disease is diagnosed by the excretion of Thymosin is the hormone secreted from thymus. At birth it weighs about 10 g, which increases in size to about Other Local Hormones 30 g during adolescence. It converts by the reticular epithelial cells of thymus (for details, angiotensinogen to angiotensin I, which is further con­ refer Chapter 18). Hence, thymus has the central position in the deve­ Erythropoietin is the glycoprotein hormone containing lopment of cellular immunity. For details of T cell 165 amino acids secreted mainly from interstitial cells development, refer ‘Immunity’. Though local hormones act locally in the tissue where they are produced, some of them have systemic effects. Female Reproductive System: Functional Anatomy, Oogenesis and Follicular Development 69. Ovarian Hormones and Control of Ovarian Functions Part D: Physiology of Conception, Pregnancy, Lactation and Contraception 71. Physiology of Contraception “To live, to love are signs of infinite things, Love is glory from eternity’s spheres. Abased, disfigured, mocked by baser mights That steal his name and shape and ecstasy, He is still the Godhead by which all can change. Describe the mechanism of sex differentiation and development in males and females. List the abnormalities of sex differentiation and understand the physiological basis of their causation. Apply the knowledge of sex determination and differentiation in understanding the physiology of reproductive system. Reproduction serves a primary goal of the nature in preservation and perpetuation of the species. The crea- tion of two sexually complete and different individuals in same species, known as sexual dimorphism is the cen- tral scheme of the nature to achieve its principal inten- tion of continuation of species through reproduction. Therefore, to appre- ciate the physiology of reproduction one should study the process of sex differentiation, development of gonads, gonadal functions, physiology of puberty and sexual mat- uration, the principles of functioning of the female and Fig. Sex Determination Sex Chromosomes Normal Chromosomal Pattern Gender is determined by the genetic inheritance of two In a normal human being, there are 46 (23 pairs) chromo- chromosomes, called sex chromosomes. The two sex somes: 22 pairs are autosomes and one pair is sex chro- chromosomes are the X chromosome, the larger one, and mosome (Fig. Females possess two X chromosomes and males have In Males one X and one Y chromosome. Hence, ideally, This is a relatively easy method to demonstrate sex chro- births of male and female children should have been matin (Barr body) in leucocytes or mucosal cells of the in equal proportion. When two X chromosomes are present, one X chromo- Y chromosomes are lighter than the sperm that con- some is functional and other X chromosome which is tain X chromosome as Y chromosome is smaller in size nonfunctional condenses to form sex chromatin. Thus, presence of Barr body generally indicates female mosomes swim faster in female genital tract and reach sex. Thus, the opportunity for these chromo- somes to fertilize ovum is more than the sperm with X Sex Differentiation chromosomes. The process of sex differentiation includes the pattern of Genetic Male development of the gonads, genital ducts, and the exter- nal genitalia. The differentiation of gender starts from sixth week of intrauterine life and continues even after birth till the When a sperm containing X chromosome fertilizes an complete maturation of the gonad of either gender is ovum, the resultant zygote develops into a genetic female achieved. Sex Determination Cell Lines of Development: Following fertilization, two Karyotyping different cell lines develop in the indifferent gonad. The one cell line forms the granulosa cells of the ovar- nique used for determining sex chromosome composition ian follicle and the Sertoli cells of the testicular semi- by employing tissue culture visualization of all chromo- niferous tubules. The differences in shape and size of chromosomes germ cells and promote their maturation, and finally in males and females help in concrete determination of guide their development into the genital duct system. Hence, instead of male gonads ovaries develop when both the sex chromosomes are X. Gonadal Sex Male Gonadal Sex In a normal genetic male, the seminiferous tubule starts to form at 6–7 weeks of gestation.

Seventy patients aged 4–28 years (median 12 therapy for newly diagnosed childhood absence epilepsy 5mg aricept visa. Introduction of ethosuximide resulted in com- mal pre-treatment liver enzymes and complete blood counts cheap 10mg aricept otc. During the generalized tonic–clonic seizure) other than typical absence sei- next 2 aricept 5 mg discount. Improved com- Afer a 16–20 week titration phase discount aricept 10 mg on line, double-blind therapy was pliance and higher ethosuximide dosages led to signifcantly higher continued until the participant either reached 2 years seizure-free ethosuximide plasma concentrations in 19 patients; 10 of these 19 pa- on blinded therapy or a pre-specifed treatment failure criterion. A double-dummy design was In these patients, the efectiveness of ethosuximide persisted over the used for children unable to swallow capsules and a blinded over-en- next 2. At the 16–20 weeks visit, mean ethosuximide daily dos- tion schemes were also used for valproic acid (up to a maximum ages and steady-state pre-dose serum concentrations were 33. If at that visit subjects continued to have clinical similarly to valproic acid (24% and 33% of patients, respectively). Conversely, for lamotrigine, lack of seizure control was the as the participant did not meet any treatment failure criteria. Treat- most common reason for treatment failure, both at the 16–20 week ment failure was defned as lack of seizure control, meeting safety and at the 12-month visit (50% and 55%, respectively). At the 16–20 exit criteria, encountering intolerable adverse events or withdrawal week and at the 12-month visit, 17% and 20% of subjects, respective- from the study for any other reason. The main efectiveness out- ly, had discontinued lamotrigine because of adverse events. Tere were no baseline demographic diferences between empirical monotherapy for childhood absence epilepsy. Freedom from failure rates of ethosuximide at the 16–20 week and 12-month visits were 53% and 45%, respectively. Effcacy in specifc syndromes other than childhood Similar retention results were found for valproic acid (58% at 16–20 absence epilepsy weeks and 44% at 12 months), whereas freedom from failure rates Tere are reports of ethosuximide being of some value in the for lamotrigine were signifcantly lower (29% at 16–20 weeks and management of patients with Dravet syndrome (severe myoclonic 21% at 12 months; P <0. Tere are no controlled studies investigating the 70 efectiveness of ethosuximide against simple partial, complex par- 60 tial or secondary generalized tonic–clonic seizures. However, recent reports suggest that ethosuximide can be efective in the treatment 50 of epileptic negative myoclonus associated with childhood focal ep- 40 ilepsy [104,105]. Weeks since randomization Browne [118] summarized these studies and found that the overall incidence of adverse efects ranged from 26% to 46%. The nal disturbances (nausea, abdominal discomfort, anorexia, vomiting superior efectiveness for ethosuximide and valproic acid over lamotrigine and diarrhoea), with a range of 4–29% across trials (median 13%), was statistically signifcant (P <0. This was in contrast with the valproic acid cohort, jects in any of the treatment cohorts in the recently conducted in which weight gain contributed to later discontinuations [91]. The Gastrointestinal effects most common adverse events reported, but not necessarily lead- The most common dose-dependent adverse efects of ethosuximide ing to treatment discontinuation, in the ethosuximide cohort were involve the gastrointestinal system: nausea or vomiting (the most gastrointestinal (particularly nausea, vomiting and stomach ache) common), stomach upset, anorexia and diarrhoea [31,91,118,119]. Hyperactivity (8%) and sleep Symptoms usually occur at the onset of therapy, are mild in severity, problems (7%) also occurred. By the 12-month visit, four children afect 20–33% of children and resolve promptly afer dose reduction in the ethosuximide group had serious adverse events that required [31,91,118]. In some patients, gastrointestinal efects are transient hospitalization (including generalized tonic–clonic seizures in two and no dose reduction is needed; in others, dividing the total daily children). Adverse events leading to ethosuximide discontinuation dosage and administering the smaller doses at meal time helps less- over the 12-month assessment period occurred in 25% of patients. Infrequently, gastrointestinal symptoms are The most common adverse events leading to discontinuation were severe enough to cause discontinuation of the drug. Ethosuximide Lamotrigine cohort Valproic acid cohort (n = 155) (n = 149) (n = 147) Short term Medium Short term Medium Short term Medium (by the 16–20 term (by the (by the 16–20 term (by the (by the 16–20 term (by the week visit) 12-month week visit) 12-month week visit) 12-month (%) visit) (%) (%) visit) (%) (%) visit) (%) General whole body Fatigue 16 17 11 12 15 18 Headache 13 15 8 9 8 12 Bacterial infection 4 5 2 3 1 1 Gastrointestinal Stomach upset 15 15 5 5 9 9 Nausea, vomiting, or both 16 19 1 1 7 8 Appetite increased 3 4 6 7 9 10 Appetite decreased 6 6 5 6 3 5 Weight increased 1 1 2 3 7 10 Diarrhoea 4 6 1 1 3 5 Neurological–behavioural–psychiatric Hyperactivity 8 8 8 8 12 16 Attention problems 4 5 5 7 11 16 Hostility 3 3 7 7 13 15 Concentration decreased 3 4 3 6 9 12 Personality change 3 4 5 7 10 12 Sleep problem 6 7 3 3 10 12 Depression 3 3 6 7 5 7 Slow process speed 1 2 4 5 5 7 Memory problem 0 0 4 5 6 7 Dizziness 6 6 3 3 1 1 Apathy 3 3 2 2 5 6 Source: Glauser et al. Ethosuximide 467 Similar to the gastrointestinal efects, drowsiness usually occurs at of myoclonic and absence seizures and transformation of absence the onset of therapy and resolves promptly when the ethosuximide into generalized tonic–clonic seizures in patients receiving etho- dose is reduced [118]. A direct relationship between behaviour- of efcacy against generalized tonic–clonic seizures. The lack of reliable methods for objectively measuring behav- ic–clonic seizures, including three in the ethosuximide group, four iour changes and the confounding infuence of polypharmacy in in the valproic acid group and one in the lamotrigine group [91]. Long-term cumulative-dose adverse efects of ethosuximide are Headaches occur in approximately 14% of children taking etho- infrequent. In contrast to the other neurological side-efects de- thisia, dyskinesias and parkinsonian syndrome) have been noted scribed, headaches do not appear to be concentration dependent, afer several years of ethosuximide treatment [109,131]. Few clinical Other adverse effects, including idiosyncratic reactions trials have examined the issue in a controlled fashion, accounting Ethosuximide therapy is not reported to cause serious endocrine for confounding variables such as serum drug concentrations, un- adverse efects [118]. The most common reac- therapy resulted in signifcant improvement in verbal and full- tions involve the skin. No subjects developed Stevens–Johnson 8 weeks of ethosuximide therapy in 17 of 37 (46%) children with syndrome. This improvement The incidence of ethosuximide-related granulocytopenia ranged was signifcantly diferent compared with a control group of patients from 0% to 7% in early studies [118]. Careful clinical did not difer signifcantly between baseline and the 12-month visit and laboratory monitoring is essential in making this distinction. Moreover, attention problems during treatment were signif- Ethosuximide-associated blood dyscrasias can involve any or all cell cantly less common with ethosuximide than with valproic acid. Only eight cases of ethosuximide-associated aplastic op episodes of psychotic behaviour manifested by anxiety, depres- anaemia were reported between 1958 and 1994, with onset 6 weeks sion, visual or auditory hallucinations and intermittent impairment to 8 months afer ethosuximide initiation [134]. The patient’s age (young on polypharmacy, with fve taking either phenytoin or ethotoin in adults in their teens or twenties) and a history of mental illness are combination with ethosuximide. Tere are currently not suximide is stopped and seizures return, possibly illustrating the enough data to assess accurately the teratogenic potential of etho- phenomenon of ‘forced normalization’. One study found that 2 out of 13 newborns recurred when ethosuximide was restarted in patients with previ- born to 10 women with epilepsy taking ethosuximide had major ous ethosuximide-related psychotic episodes. The mothers of these two seriously afected newborn in- in young children with no previous history of psychiatric disease fants were on ethosuximide in combination with phenobarbital in receiving ethosuximide for typical absence seizures [118]. In another small series, one of No evidence of ethosuximide-associated seizure exacerbation fve infants born to a mother taking ethosuximide was malformed has been found in most studies [80,110, 115,117,128]. The management of etho- adolescence is approached the risk of generalized tonic–clonic sei- suximide overdose involves life support measures, symptomatic zures increases [140,141]. Life support measures involve initial tients with typical or atypical absence seizures not controlled on and immediate evaluation and stabilization of the patient’s airway, ethosuximide or valproic acid monotherapy or (ii) patients with breathing and circulation. Administration of activated charcoal as an aqueous slurry partial or secondary generalized tonic–clonic seizures. The efectiveness of activated charcoal is greatest if given ful are discussed in the section ‘Efcacy in specifc syndromes oth- within 1 h of an ethosuximide overdose [136]. In many of these syndromes, dose of activated charcoal is 1 g/kg of weight for infants up to 1 year ethosuximide is usually combined with other drugs possessing a old, 25–50 g in children between 1 and 12 years old and 25–100 g in broader spectrum of antiseizure activity. If emesis or rapid deterioration of consciousness occurs or is impending, only Dose and titration rates personnel skilled in airway management should administer acti- A common starting dose for children is 10–15 mg/kg/day. The con- sequent titration is performed according to the patient’s clinical traindications for the use of activated charcoal are a patient with an response. In older children and adults, ethosuximide is ofen in- unprotected airway or if the therapy increases the risk or severity of itiated at 250 mg/day and increased by 250-mg increments until aspiration [137]. Ethosuximide can be ad- Gastric lavage with a large-bore orogastric tube may be consid- ministered either as once-, twice- or even thrice-daily dosing (with ered if a potentially life-threatening amount of ethosuximide has meals) to maximize seizure control while minimizing adverse ef- been ingested and the procedure can be performed within 1 h of the fects. Gastric lavage should not be employed routinely adults varies from 3 days to every 12–15 days. When used in elderly Haemodialysis may also be useful in the treatment of an ethosux- patients, ethosuximide should be titrated using smaller increments imide overdose. This is based on an observed extraction efciency with longer intervals between changes. The time to reach steady- of 61–100% in one study of four patients with chronic renal disease state concentration following a dosage change is 6–7 days for chil- (supported by haemodialysis) who received a single dose of 500 mg dren and 12 days for adults. In this study, the elimination If the clinical situation warrants discontinuing ethosuximide half-life of ethosuximide was reduced by dialysis to an average of (e. Tere have been no reports of haemoperfusion use in of absence seizures), then gradual reduction over 4–8 weeks is rec- ethosuximide overdose. If necessary, abrupt discontinuation is probably safe resis have little place in the treatment of ethosuximide overdose be- because of the long half-life of ethosuximide.

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