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Non-commercial offcial name Patented trade name Grand mal and psychomotor seizures Bromides Bromides Phenobarbitala Luminal Methobarbital Mebaral Diphenylhydantoina Dilantin Mesantoin Mesantoin Ethotoin Peganone Primidonea Mysoline Phenacemide Phenurone Methsuximidea Celontin Acetazolamideb Diamox Petit mal Trimethadioneb Tridione Paramethadionea Paradione Phensuximidea Milontin Ethylmethylsuccinimide Zarontin Quinacrine hydrochloride Atabrine Metharbital Gemonil Source: From Lennox 1960 [16] order discount cialis sublingual online. Phenurone and Diamox were noted to be often effective against petit mal as well purchase cialis sublingual with mastercard, and phensuximide to be often effective against grand mal cialis sublingual 20 mg with amex. In addition to the above licensed drugs buy cialis sublingual pills in toronto, each edition of the book has listed drugs in early clinical development: 1st edition: eterobarb, levetiracetam, losigamone, ralitoline, remacemide, stiripentol, taltrimide, tiagabine, zonisamide. International League Queen Square, 1857–1939: a mirror of the frst phase of the modern history of Against Epilepsy: A Centenary History. Progress report on new antiepileptic May 1857: Sir Charles Locock, president in the chair. On Epilepsy and Epileptiform Seizures, Teir Causes, Pathology and lepsy Res 1996; 25: 299–319. Both are topics that only the battle har- has been the greatest single individual contribution to the subject. Strong and divergent views are ofen held, Afer Jackson, less infuential authors suggested various alterna- and passions excited, but not much clarity. Over a period of several decades, with the work have periodically bubbled to the surface, a reiteration that could particularly of Fritz Dreifuss, a defnition and classifcation system have been avoided with more historical knowledge. The It could be argued that the modern defnitions of epilepsy and urgency for standardization in the feld was recognized and in the in- epileptic seizures were developed in the 1870s with the writing troduction to the published dictionary it is stated that: ‘The situation of John Hughlings Jackson. With astounding prescience, in 1870 has deteriorated with the growth of published information; terms are he defned an epileptic seizure as the clinical correlate of ‘an occa- frequently not defned and may have diferent meanings for author sional, sudden and excessive discharge of grey matter’ [1], and in and reader. He recognized Masland, Pond, Collomb, Saradzisvilli, Broughton, Valasco Suarez, that the beginning of the seizure (the aura) gives a clue to the sei- and Wada) and then by a wider group of experts from 16 countries. He also devoted pages to a discussion of the nature and therein, for the frst time, many of the types of epilepsy and epileptic pathophysiology of epilepsy, and based his defnitions and classi- seizures and other terms related to epilepsy were formally defned. Study Defnition of epilepsy Defnition of epileptic seizure 1973 [3] A chronic brain disorder of various aetiologies A cerebral attack resulting from an excessive neuronal characterized by recurrent seizures due to excessive discharge discharges of cerebral neurons, associated with a variety of clinical and laboratory manifestations 2001 [4] A chronic neurologic condition characterized by A manifestation of epileptic (excessive and/or recurrent epileptic seizures hypersynchronous), usually self-limited activity of neurons in the brain 2006 [5] A disorder of the brain characterized by an enduring A transient occurrence of signs and/or symptoms due predisposition to generate epileptic seizures and by to abnormal excessive or synchronous neuronal activity the neurobiologic, cognitive, psychological and social in the brain consequences of this condition. The defnition of epilepsy requires the occurrence of at least one epileptic seizure 2014 [6] A disease of the brain defned by any of the following conditions: (1) At least two unprovoked (or refex) seizures occurring >24 h apart; (2) one unprovoked (or refex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndromea aThe 2014 taskforce report also added that epilepsy should be considered to have resolved when an individual: (a) exceeds the age of an ‘age-dependent epilepsy syndrome’ or (b) who have remained seizure-free for the last 10 years and off antiseizure medicines for at least the last 5 years. The defnitions of ep- Jackson made another extremely important point when he dis- ilepsy and epileptic seizures were reformulated. He used the analogy of tions, claiming that there was ‘little common agreement’ on the a classifcation of plants. The scientifc classifcation was based on defnitions of epilepsy and seizures, although it is not clear why this taxonomy and is what a botanist might use, by providing a listing of was thought. It was also stated that the 2001 glossary defnition was natural classes for instance of species, genera, phila, and so on. The ‘preliminary’, although there was nothing to suggest this in the 2001 practical classifcation, on the other hand, is what a gardener might publication. Ten, in 2014, the same taskforce [6], some might feel use and is ‘such an arrangement [that] goes by what is most superf- rather ingenuously claiming that the 2005 defnition of epilepsy was cial or striking’. The practical classifcation facilitates the identifca- a ‘conceptual’ defnition, decided that this could be ‘translated’ into tion and the application of knowledge for utilitarian purposes but, a new ‘operational defnition’ (a practical clinical defnition) which as Jackson pointed out: ‘[it can] not be trusted as a natural classif- was to supersede previous eforts. The defnition of epilepsy has evolved, and versus scientifc appears in various places in Jackson’s oeuvre, and possibly not for the better, and one wonders really what is the point the importance of this distinction was clear to him and to his read- of these incessant changes. This stimulated much activity Defnition (Terminology) and Classifcation in Epilepsy 3 Table 1. He embarked on a series of classifcation summary form of the classification was also published at the end schemes in the 1960s and 1970s which were to become universally of the 1964 version, but it was clear that Gastaut disliked this adopted. They debated for two days, until to Epilepsia as part of the programme of the 1969 New York confer- it seems exhaustion set in. After two days, a new draft was cre- ence and then republished in an identical form in Epilepsia in 1970 ated which was then submitted to a newly formed Commission (Table 1. This commission met in May 1969/1970 versions, notably changes to the terminology of absence Table 1. With complex symptomatology (automatism, ideational, psychosensory, psychomotor symptoms) C. Absences may occur alone, or in combination with myoclonic jerks, or with increase or loss of postural tone, or with automatisms B. Generalized convulsive seizures, in the form of tonic, clonic, tonic-clonic and/or myoclonic attacks 3. Unilateral or predominantly unilateral seizures (tonic and/or clonic) in children 4. This summary form of the 1964 classifcation was disliked by Gastaut and no summary form was included in the 1969/1970 schemes. Electro- Electro- encephalographic encephalographic interictal Anatomical Clinical seizure type seizure type expressiona substrate Etiology Age 1. Partial seizures with elementary symptomatology (generally without impairment of consciousness) 1. With motor symptoms Local contralateral Local contralateral Various cortical Usually related to Possible at all ages focal motor (without discharge discharges and/or subcortical a wide variety of but more frequent march), including localized starting over the regions local brain lesions with increasing age epileptic myoclonus corresponding corresponding (cause known, Jacksonian versive (generally area of cortical with functional suspected or contraversive) postural representation (not representation in unknown). With special sensory or somatosensory symptoms (i) somatosensory (ii) visual (iii) auditory (iv) olfactory (v) gustatory (vi) vertiginous 3. Partial seizures with complex symptomatology (generally with impairment of consciousness; may sometimes begin with elementary symptomatology) 1. With impaired Unilateral or Unilateral or Usually cortical As above As above consciousness only bilateral discharge, bilateral, generally and/or subcortical diffuse, or focal in asynchronous temporal or 2. With cognitive temporal or fronto- focus; usually fronto-temporal symptomatology temporal regions in the temporal regions (including (i) with dysmnesic region(s) rhinencephalic disturbances (conscious structures), amnesia, ‘déjà vu’, ‘deja unilateral or vecu’) bilateral (ii) with ideational disturbances (including ‘forced thinking’, dreamy state) 3. Compound forms Defnition (Terminology) and Classifcation in Epilepsy 5 Electro- Electro- encephalographic encephalographic interictal Anatomical Clinical seizure type seizure type expressiona substrate Etiology Age C. Partial seizures secondarily generalized (all forms of partial seizures, with elementary or complex symptomatology, can develop into generalized seizures, sometimes so rapidly that the focal features may be unobservable. These generalized seizures may be symmetrical or asymmetrical, tonic or clonic, but most often tonic–clonic in type) Above discharge As above As above becomes secondarily and rapidly generalized 2. Generalized seizures, bilateral symmetrical seizures or seizures without local onset Convulsive or non-convulsive Bilateral, essentially Bilateral, essentially Unlocalized No cause found or: All ages symptomatology, without signs synchronous and synchronous (? With rhythmical 3 Spike and waves and/ As above As above (organic Especially in (a) Simple absences, c/s spike and wave or dpolyspikes and etiology is usual children with impairment of discharge (‘petit wave discharges consciousness only mal’ or atypical (b) Complex absences absence) with other phenomeno associated with 2. Without 3 c/s spike More or less As above As above (organic Especially in impairment of and wave (variant rhythmic discharges etiology is usual; children consciousness: of ‘petit mal’ or of sharp and slow cerebral metabolic (i) with mild clonic atypical absence): waves, some times disturbances components (i) low-voltage asymmetrical superimposed on (myoclonic fast activity previous brain lesion absences) or rhythmic may be important) (ii) with increase of discharge at 10 postural tone or more c/s, or As above As above As above (retropulsive (ii) more or less absences) rhythmic (iii) with diminution discharge of or abolition of sharp and postural tone (atonic slow waves, absences) sometimes (iv) with automatisms asymmetrical (automatic absences) (v) with autonomic phenomena (e. Bilateral massive epileptic Polyspike and waves Polyspike and waves, As above As above All ages myoclonus (myoclonic jerks) or, sometimes, spike or spike and waves and waves or sharp sometimes sharp and and slow waves slow waves (continued) 6 Chapter 1 Table 1. Infantile spasms Flattening of the Hypsarhythmia As above As above (cerebral Infants only hypsarhythmia metabolic during the spasm, or disturbances exceptionally, more superimposed on prominent spikes and previous brain lesion slow waves may be important) 4. Clonic seizures Mixture of fast (10 Spike and waves As above As above Especially in c/s or more) and slow and/or polyspike and children waves with occasional wave discharges spike and wave patterns 5. Tonic seizures Low voltage fast More or less As above As above (organic Especially in activity or a fast rhythmic discharges etiology is usual) children rhythm (l0 c/s or of sharp and slow more) decreasing waves, sometimes in frequency and asymmetrical increasing in amplitude 6. Tonic–clonic seizures (‘grand Rhythm at 10 or Polyspike and waves As above As above Less frequent mal’ seizures) more c/s, decreasing and/or spike and in young in frequency and waves or, sometimes, children than increasing in amplitude sharp and slow wave other forms during the tonic discharges of generalized phase, interrupted by seizures. Atonic seizures sometimes associated with myoclonic jerks (a) of very brief duration Polyspike and waves Polyspike and wave As above As above (organic Especially in (epileptic drop attacks) (more waves than etiology is usual) children in the myoclonic polyspike and wave) (b) of longer duration Rhythmic spike and Polyspike and waves (including atonic wave (3–1 c/s) or and/or spike and absences) mixture of fast and waves or, sometimes, slow waves with sharp and slow wave occasional spike and discharges wave patterns 8. Akinetic seizures (loss of Rhythmic spike and Polyspike and waves As above As above Especially in movement without atonia) wave (3–1 c/s) or and/or spike and children mixture of fast and waves or, sometimes, slow waves with sharp and slow wave occasional spike and discharges wave patterns Source: Gastaut 1969 [12]. Defnition (Terminology) and Classifcation in Epilepsy 7 seizures (typical/atypical changed to simple/complex), the inclu- until then, as he realized that a system (a network) involving wide sion in 1969/1970 of infantile spasms as a generalized seizure type, areas of cortex and deep grey matter and other connections under- the absence/presence of alteration of consciousness mentioned with pinned many partial seizures (for a contemporary discussion of this simple/complex partial seizures, and the exclusion of the 1964 cate- topic see [10]). This distinction has now regrettably been lost again gories of erratic neonatal seizures. The seizures were compilation of knowledge has been brought in line with the subdivided into two fundamental groups in both schemes: partial state-of-the-art technology without extrapolating to what can- and generalized seizures in Gastaut’s, and partial and central in not be observed, but cognizant of the evanescence of any living Symonds’. First, the parameters of anatomy, age and a narrowly limited or even quite difuse cortical (the most accessible and aetiology were removed. Second, Seizures in which the clinical features do not include any sign or symp- partial seizures were separated into simple and complex cate- tom referable to an anatomical and/or functional system localized in one gories depending on whether consciousness was disturbed, and hemisphere, and usually consist of initial impairment of consciousness, this differed from the usage of simple and complex in the 1964 motor changes which are generalized or at least bilateral and more or and 1969/1970 classifications. The categories of generalized sei- less symmetrical and may be accompanied by an ‘en masse’ autonomic zures also changed. It spheres; and in which the responsible neuronal discharge takes place, if remains the ofcially recognized classifcation of epileptic seizures not throughout the entire grey matter, then at least in the greater part of it and simultaneously on both sides. With motor signs: Local contralateral discharge starting over the Local contrarateral discharge (a) focal motor without march corresponding area of cortical representation (b) focal motor with march (not always recorded on the scalp) (c) versive (d) postural (e) phonatory (vocalization or arrest of speech) 2. With somatosensory or special sensory symptoms (simple hallucinations): (a) somatosensory (b) visual (c) auditory (d) olfactory (e) gustatory (f) vertiginous 3.

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Parviz Toosi, Afshin Sadighha, Ali Sharifan and Gita use within 6 months of entry in the study, photosen- M eshkat Razavi: A comparison study of the effcacy and side effects of different light sources in hair removal: sitivity or seizure disorder triggered by infrared Lasers M ed Sci. Arch Dermatol 124(6):869–871 Carboxytherapy in Aesthetic 43 Medicine Nina Koutná 43. It is soluble in water depending on the pressure South American information sources. Through normal venti- possibilities have been shown including those in aes- lation of 6 L of the air per minute, 250 mL of O2/min is thetic medicine. In hyper- skin rejuvenation, in the treatment of certain types ventilation, 4–5 L of O2/min is consumed and 4–4. The method is “natural” which makes it attractive abdominal cavity, without any toxic effect [1–3]. In later leads to better oxygenation and overall improvement M iddle Ages, the Benedictine abbey was found in the of local metabolism – one of the main mechanisms of place, and although it was soon devastated by wars, later the effect of carboxytherapy. Such gas known in clinical praxis as a more reliable indicator of can mix with deep sources of water usually of meteoric preoperative ischemia and postoperative outcome of origin, beside trace components. Pure gas springs of revascularization than hemodynamic, Doppler-derived temperature under 100°C are called “mofets” [7]. Sometimes water and gas springs create interesting In another work, Ambrosi and Lafaye [14] proved natural phenomena, burbling muddy lakes colored by by thermography that after the 18 days lasting thermal minerals (e. In certain sites, naturally based dicative patients showed more than 20% warming of spas had been established during history (Spa Royat in the lower extremities while 2 had smaller warming and France, M assif Central where local gas spring of power 7 were negative, showing slight cooling. After the cure of local gas baths (dry that of Spa Royat in France, where frst Roman spa baths) of the wounded extremity, 22. In der- water bathing therapy could be included in angiogenic matology, the method is very useful in wound healing therapies associated with neovascularization. In spas, depending on Some physicians experiment with the treatment of nail 550 N. Koutná disorders, vitiligo, or erysipelas with success, but these Liebaschoff, Cadic, etc. As hair state is also the subject respiratory insufciency, severe renal failure, chronic of aesthetic medicine, the treatment of the hair fall and congestive heart failure, patients treated by carboanhy- alopecias should be also added to this part, similarly like drase inhibitors (e. However, in aesthetic frequent contraindications are pregnancy and breast- medicine, because of sometimes surprisingly impres- feeding (mainly because of legal reasons). These are frst of all mechanical undermining the possibilities of carboxytherapy use were gradually by the gas fow (similarly like in needle subcision, e. Third, presumably there is also some damage connective spaces with vascular structures and slight infuence of temporary acidosis [23, 24]. It was also found that improvement of proof the real role of these factors of hypothetically high skin elasticity after carboxytherapy measured by importance in experiments either in vitro or in vivo. To simulate conditions of carboxytherapeutical rare indications of carboxytherapy proceeded in South treatment (ideally including the mechanical force of the America, especially in Brazil, quite likely because of gas fow) in cell culture or artifcial skin model is cur- the versatility and art of local physicians. Thanks to rently not possible and we can only speculate, backed by these experiences mixed with those from the other areas the results of other experiments. There are numerous of the world (Brandi, Parmigiano, D’Aniello in Italy, papers describing the effects of mechanical forces 43 Carboxytherapy in Aesthetic Medicine 551 (usually stretching, but also pressure) on dermal fbro- stretch. Fibroblasts showed maximal expression of blasts, keratinocytes, and melanocytes [26–32]. Fibroblasts release cytokines and because the gas is “metabolized fast,” from praxis we growth factors of autocrine and paracrine effects. Also after medium insuffation of the activity has infuence on keratinocyte growth and differ- eyelids sometimes we observe the rest of the gas stay- entiation through fbroblast secretion of keratinocyte ing in the tissue for many hours. In redistribution of ß1-integrins in clusters on the basal carboxytherapy, we can expect more or less uniaxial cell membrane, although the overall amount of this stretching in the case of skin rejuvenation, treatment of integrin subset was not changed. Clustering of ß-1 wounds and scars, and “multiaxial” stretching and pres- integrins was described also for other cell lines sure in the treatment of cellulite. Generally, it was pos- (endothelial cells, fbroblasts, osteoblasts, heart muscle tulated that mechanical stretching leads to cellular cells) indicating a universal response to this stimulus. Koutná of apoptosis and that increase in cell numbers of the and adjustable fow of the gas. They contain mechani- culture in response to mechanical stress was, at least in cal and anti-bacterial flters assuring the sterility of the part, due to a suppression of apoptosis. In the paper of gas, and prewarm the gas (the administration of the Ferreira et al. M oreover, after intra- the combination of carboxytherapy and mesotherapy – dermal gas injection the collagen was more compact M esofux® (PromoItalia). These fndings can be reached with any apparatus and that the results are interesting, in concert with Kippenberger et al. It is true boxytherapy as a “natural antiaging” treatment which that cellulite or scars can be basically treated by any connects the effects on angiogenesis and improvement carboxytherapeutic device (although with different of the trophic as well as the effects induced in the cells levels of comfort for the patient), but if one wants to by mechanical powers of the gas fow and gas volume. The injection of the gas one can try to apply to are safe only for balneotherapy and physiotherapy. In himself or herself, often the frst self-experience with aesthetic medicine and especially in the treatment of the treatment happens on the workshops. There is a the face we need a more precise tool, with ability to difference in the treatment of different areas, by differ- apply very different amounts of the gas in different ent machines, etc. The one with smaller pres- After explaining the course of the treatment to the sure, and thus “softer,” with not so centered power of patient including possible local sensations which may the gas led to visibly smaller results and experienced occur during the application (feelings like slight or more patients noticed not only the difference in feeling of intensive burning, strange feelings or pressure in the the gas fow in the tissue during the application but treated area, feelings like when cold water fows in the also smaller effect after the “softer” device (unpub- area, these all lasting for cca dozens of seconds), lished observation, Koutna). Then the parameters (gas Some South American devices (Carbtek Advanced® fow – velocity, expected time, type of the treatment, by Estek) are able to work also in intermittent, pulsing etc. After the disinfection of the area (this can be 43 Carboxytherapy in Aesthetic Medicine 553 554 N. This is the easiest and proper solution, however, effect by itself, the method is very safe and possibility of with the disadvantage for the patient because he or she folliculitis or any pyodermia as a side effect is very feels the gas together with the pain resulting by the nee- unprobable), the gas injection is applied. This can be achieved either by frst pressing applied as superfcially intradermally as possible. Local the foot switch, wait some seconds for the full gas fow skin bleaching coming just in the moment when the gas (this, in case if one is not sure can be felt if the open is injected can be observed, changing fast into redness needle or just tube is put close to the skin of the ventral (Fig. If we inject more gas (depends on the area 43 Carboxytherapy in Aesthetic Medicine 555 50 mL per injection spot, depending on the state, gas fow, and tolerance of the patient. After fnishing the treatment there still can be capil- lary bleeding in some injection sites, requiring clean- ing by disinfection solution, momentary compression, and sometimes (the legs) a small piece of sticking plas- ter. As the method is injectional, there can be occa- sional bruising (usually more often on the legs and neck than in the face). M ake-up is not recommended to apply sooner than 20 min after the treatment, however not every patient respects this. After carboxytherapy is performed on the forehead or in capillitium, some patients can feel sensitivity in Fig. These sensa- tions usually do not last long, but headache can disturb sensitive patients for even 24 h. Sometimes there is a and indication, as will be discussed later) or inject less feeling of heavy legs in the treatment of cellulite, last- superfcially, usually “running” emphysema in stripes ing for 2–3 days. The gas, however, tends day of the treatment, but it is good to discuss it with the to “run” not simply in the direction of the needle as one patient and recommend avoiding extreme body posi- would expect, but often also in the direction of the low- tions, exhausting exercising, or certain more exotic est resistance of the surrounding tissue (so also deeper). Redness and warmness of the area can be seen during the application on the skin of dis- can be present for longer time, but usually not longer posed patients (Fig. Some patients tend to faint during any injection For the treatment of hair disorders, wounds, or some treatment, with carboxytherapy being no exception.

Potential secondary renal efects order cialis sublingual 20mg on-line, which may be caused fessional and follow-up testing every 6 months buy cheapest cialis sublingual. Additional testing includes fuorescein angiograms discount cialis sublingual online master card, currence of discoloration of the skin which appeared as blue pig- ocular coherence tomography cialis sublingual 20mg lowest price, perimetry and electroretinograms. The mechanisms of the pigment changes, the magnitude generally reached a plateau during open-label treatment [76]. Until these during pregnancy or by nursing women only if the potential beneft knowledge gaps are adequately addressed, it is unlikely that current outweighs the potential risk for the fetus or the infant. Current place in therapy Clinical studies have documented the efcacy of retigabine as ad- References junctive therapy in adults with refractory focal seizures. Anticonvulsant properties of D-20443 in stages of the medical management of localization-related epilepsies, genetically epilepsy-prone rats: prediction of clinical response. Neurosci Lett 1995; for example when sodium channel blockers, such as carbamaze- 195: 77–80. D-23129: a potent anticonvulsant in the amygdala kindling model of complex partial seizures. In particular, retigabine should be initiated grad- the 6 Hz psychomotor seizure model of partial epilepsy. Epilepsy Res 2001; 47: ually, for example with a starting dose of 300 mg/day, which can 217–227. Development and reversal of contingent inefcacy and toler- be increased weekly in 150-mg increments. Lamotrigine treatment during amygdala-kindled concentration-related adverse efects such as dizziness. The results seizure development fails to inhibit seizures and diminishes subsequent anticon- of double-blind, placebo-controlled studies as well as open-label, vulsant efcacy. Carbamazepine, but not val- proate, displays pharmacoresistance in lamotrigine-resistant amydala-kindled is 600–900 mg/day. Retigabine decreases behavioral and electrographic bly 20% of patients will require higher dosages of up to 1200 mg/ seizures in the lamotrigine-resistant amygdala kindled rat model of pharmacore- day. Antiepileptogenic efect of D-23129 (retigabine) in with renal impairment or moderate to severe hepatic impairment, the amygdala kindling model of epilepsy. Epilepsia 2008; 49: Because retigabine is associated with a relatively low potential for 1777–1786. Peripheral nerve hyperexcitability due trigine levels may decrease by about 20% on average. Diferential expression of genes encoding subthreshold-operating voltage-gated K+ channels in brain. Very few elderly patients, however, were included in the stud- ies, and the safety profle of retigabine has not been fully evaluated Neurosci 2004; 24: 1236–1244. Pharmacological characterisation The possible occurrence of skin and retina pigment changes, of acid-induced muscle allodynia in rats. Naunyn-Schmied Arch Pharmacol safety issue that currently limits the indication and clinical use of 2004; 369: 382–390. The anticonvulsant retigabine attenuates nocicep- restricted the indication to adjunctive therapy for adults with re- tive behaviours in rat models of persistent and neuropathic pain. Eur J Pharmacol fractory focal seizures where other appropriate drug combinations 2003; 460: 109–116. J Pharmacol Exp testing and dilated fundus photography, and may also include fuo- Ter 2005; 314: 282–92. Efect of the new antiepileptic drug rescein angiograms, ocular coherence tomography, perimetry and retigabine in a rodent model of mania. The anticonvulsant retigabine potently suppresses epilepti- J Pharmacol 2006; 149: 747–753. Efects of retigabine (D-23129) on difer- German Neuroscience Society, Göttingen, Germany, 29 March to 1 April 2007. J Neurophysiol pamine release triggered by depolarization and pre-synaptic muscarinic receptor 2006; 95: 3480–3495. N-Glucuronidation of the antiepileptic drug potassium currents and native neuronal M-type potassium currents by the an- retigabine: results from studies with human volunteers, heterologously expressed ti-convulsant drug retigabine. The new anticonvulsant retigabine favors potential role in enterohepatic circulation. Randomized, double-blind, place- channels, contribute to the somatic medium afer- hyperpolarization and excitabil- bo- controlled trial of ezogabine (retigabine) in partial epilsy. Efcacy and safety of adjunctive ezoga- nels control interspike interval in hippocampal interneurons. Retigabine strongly reduces re- adults with partial-onset seizures: integrated analysis of three pivotal controlled petitive fring in rat entorhinal cortex. Safety and efcacy of ezogabine (retigabine) ent patterns of epileptiform activity induced by 4-aminopyridine in rat entorhinal in adults with refractory partial-onset seizures: Interim results from two ongoing cortex hippocampal slices. Blue-gray mucocutaneous dis- of the anticonvulsant retigabine in acute manic patients. Higher doses have been used, up to 4800 mg/day Dosing frequency Twice daily Signifcant drug Phenobarbital, carbamazepine, phenytoin, primidone and vigabatrin interactions may cause a slight to moderate decrease in serum rufnamide levels. Valproic acid increases serum rufnamide levels (especially in children – up to 70%). Rufnamide may slightly decrease the serum levels of carbamazepine and lamotrigine, and increase slightly those of phenytoin and phenobarbital. Rufnamide decreases the serum levels of oral contraceptive steroids and triazolam Serum level monitoring Tere is insufcient information on the value of monitoring serum rufnamide levels Target range Not clearly defned Common/important side Dizziness, headache, nausea, somnolence, diplopia, blurred vision, effects fatigue and ataxia Main advantages Robust efcacy in the Lennox–Gastaut syndrome trial Main disadvantages Modest efcacy in focal seizures (not currently approved for this indication) Mechanism of action Limits excessive fring of sodium-channel dependent action potentials Oral bioavailability Up to 85% in the fed state, but decreases with increasing dosage within the clinically used dose range. Bioavailability increases by about 40% when the drug is taken with food Time to peak levels 4–6 h Elimination Primarily by hydrolysis of the carboxamide group The Treatment of Epilepsy. Increases with increasing dosage, because actual bioavailability decreases as dose is increased Elimination half-life 8–12 h (shorter in patients co-medicated with enzyme-inducers) Plasma clearance On average about 90 mL/h/kg in adults at a dosage of 45 mg/kg. Increases with increasing dosage, and is higher in children than in adults Protein binding 30% Active metabolites None Comment A potentially valuable drug. In February 2004, Eisai Company Ltd acquired the rights to develop rufnamide for epilepsy from Novartis. Of two monotherapy trials in adults with focal seizures, one was positive and the other did not meet the primary end-point. In a trial in Lennox–Gastaut syndrome, a relatively large efect size was 200 demonstrated. In addition, there has been a negative trial in pa- tients with primary generalized tonic–clonic seizures and another negative trial in the add-on setting in children with focal seizures. A pi- lot trial in patients with diabetic neuropathic pain was negative but 0 suggestive of a small efect size. Rufnamide has a chemical formula of C10H8F2N4O, which corresponds to a molecular weight Pharmacology of 238. The drug does not show any hygroscopicity; no water was absorbed Activity in experimental models of seizures and epilepsy by the drug when placed in an environment of up to 100% relative The activity profle of rufnamide in experimental models has been humidity. Pharmacokinetics Repeated dosing for 5 days at a single dose of 6 mg/kg orally did not induce tolerance to the anticonvulsant efects of rufnamide. Absorption and bioavailability The anticonvulsant efect in the maximal electroshock test was Rufnamide is relatively slowly absorbed from the gastrointesti- maintained for 4 h in mice and 8 h in rats [8,9,10]. However, it was hardly efective in the gly- dissolution into gastrointestinal contents [13]. It has also shown efectiveness in reducing seizure plasma rufnamide concentration and dose during treatment with a frequency in rhesus monkeys with chronic alumina foci in the dose of 3600 mg twice daily was approximately half that recorded at motor cortex. Hippocampal and cortical aferdischarges induced a dose of 400 mg twice daily [13]. It is also partially efective in the strychnine test, although availability during multiple dosing has not been clearly established, it appears that, among the various seizure models tested, strych- it is recommended that rufnamide always be taken at meal times. In contrast to rufnamide, phenytoin did not provide protection Distribution against various types of chemically induced seizures [12]. The plasma protein binding of rufnamide is low, at about 26–34% In most animal models, the therapeutic index of rufnamide was [13]. As expected, larger Vd/F values Although the precise mechanisms of action of rufnamide are in- have been measured in subjects receiving higher dosages, as a result completely known, based on in vitro studies the principal mecha- of the dose-dependent decrease in bioavailability [13]. Rufnamide nism of rufnamide’s antiepileptic activity appears to involve mod- is evenly distributed between erythrocytes and plasma. An additional potential and rabbits afer administration of radioactive rufnamide (Eisai, mechanism is represented by inhibition of responses at the gluta- data on fle). The concentrations in the embryo and the amniotic mate receptor subtype mguR5, which is observed at high concen- fuid were about half of those in the maternal blood afer 24 hours.

Mechanical ventilation: For respiratory paralysis in cases of neurotoxicity by Cobra and Krait purchase cialis sublingual 20mg free shipping, this form of therapy is life saving discount cialis sublingual amex. Blood transfusion cheap cialis sublingual 20mg, blood components generic cialis sublingual 20mg without a prescription, volume expanders, peritoneal dialysis are needed depending on the clinical situation. It is to be remembered that no amount of heparin, blood components, antifibrinolytics or coagulation factors can help till there is circulating venom in victims body. History of snake bite and fang marks are not must to diagnose snake envenomation (e. Cobra, Krait, Russell’s Viper and Saw scaled Viper account for majority of poisonous snake bites in India. In areas known for Krait bites when a perfectly normal person, sleeping on floor reports early morning with vomitings, abdominal pain and bulbar palsy, it should be diagnosed as Krait envenomation, unless proved otherwise. Don’t underestimate local complications of snake bites, it may lead to gangrene and amputation. Don’t ignore bite by small snakes, bite after eating prey or bite after several strikes–all such bites are capable of severe envenomation. Bacteriological studies of venom and mouth carriers of wild Malayan pit vipers in southern Thailand. Scorpion Sting Scorpion sting is a dramatic, life threatening medical emergency usually encountered in villages of tropical and subtropical countries. Bawaskar from Raigad in Maharashtra has contributed immensely in this field and has helped to reduce mortality. They are Mesobuthus tamulus (Indian red scorpion) and Palamneus Gravimanus (Indian black scorpion or Ingali). It is found in Maharashtra, Karnataka, Andhra Pradesh, Tamil Nadu, Gujarat and Pondicherry. They are commonly found in underground burrows, crevices in dwellings, under debris and logs of wood, banana, sugarcane and coconut plantations and paddy husks. A scorpion sting does not always mean envenomation because it can control it’s ejaculation of venom. Metabolic effects mediated by alpha receptors stimulation are suppression of insulin secretion, hyperglycemia, hyperkalemia, free fatty acid accumulation and elevation of free radicals (responsible for myocardial damage). Direct toxic effect on neurons: explaining seizures and encephalopathy in few cases. Skin and subcutaneous tissue: Toxin of Indian red scorpion has little or no effect on skin but the black scorpion causes severe skin manifestations. Other manifestations not commonly seen in India are pancreatitis, hepatic necrosis and intravascular hemolysis leading to acute renal failure. Autonomic storm: Cholinergic storm is initial and short lived while adrenergic storm is subsequent and more prolonged. In those patients who have severe local pain, no further systemic manifestations (like autonomic storm, pulmonary edema, etc. The local pain in such patients may reappear during recovery from systemic complications. Sometimes local edema, sweating, pinhead bleed, local fasciculations and spasm of surrounding muscle is seen. Presence of local pain in the beginning and appearance of local pain after treatment, which was absent in the beginning, both are good prognostic indicators. The former indicates nonpoisonous or nonbuthus sting and later indicates recovery from envenomation. Cholinergic storm: Patient initially shows signs and symptoms due to excess acetylcholine outpouring, i. Adrenergic storm – Inotropic phase: Patient manifest with tachycardia, hypertension, cold extremities and arrhythmias. Adrenergic storm–Hypokinetic phase: Hypertensive stress on myocardium, direct myocardial toxicity and catecholamine induced coronary spasm9 contributes to myocardial dysfunction and leads to left ventricular failure causing important clinical feature of scorpion envenomation, i. Tachypnea and intractable cough can be early indicators of developing pulmonary edema. Recovery phase: During recovery phase child’s general condition improves, extremities become warm and pulse volume increases. Sometimes hypotension can be seen during recovery, which is attributed to exhausted catecholamine stores of body, which are yet to be replenished in natural course (and does not need inotrope support). Another feature suggestive of recovery is appearance of local pain, which was absent in the beginning. Local pain relief: Patients with systemic manifestations have mild, tolerable pain and needs no treatment. Fluid therapy: Early cholinergic storm having vomitings and profuse sweating causes fluid loss and can lead to hypotension. Depending on clinical condition of child, either oral or parenteral fluids are administered. Various drugs used are Prazocin, Sodium Nitroprusside, Nitroglycerin or Isosorbide dinitratre. Prazocin: This postsynaptic, competitive, alpha-1 adrenergic receptor antagonist is the first line management of scorpion envenomation. It reverses both inotropic and hypokinetic phases as well as metabolic effects of depressed insulin secretions. First dose phenomenon (leading to hypotension) can be prevented by plenty of oral fluids, not allowing child to sit or stand and monitoring of blood pressure–every 30 minutes for first 3 to 5 hours. Prazocin should be given irrespective of blood pressure in presence of good hydration. Appearance of wide pulse pressure is an early clinical indicator of reduction of preload and afterload. Oral prazocin is cheap, fast acting, free from anaphylaxis, highly effective and easily available. Bottle should be wrapped with opaque paper or cloth and no other drug should be added to infusion. Atropine: It is given for symptomatic relief from clinical effects of cholinergic storm. Corticosteroids: Steroids potentiate the toxic effects of excess catecholamine on myocardium. Lytic cocktail: Potentiates the effects of Scorpion venom, interfere with respiratory reflexes and prolongs hypotension. Severe local pain at the site of sting is unlikely to progress to systemic manifestations. Autonomic storm is the basic pathogenetic mechanism leading to all clinical features and complications of Scorpion sting. Warming up of extremities and appearance of local pain are suggestive of recovery. Oral prazocin is an antidote of Scorpion venom and should be used at the earliest. Avoid using atropine, steroids, lytic cocktail, morphine, nifedipine and captopril. Management of Cardiovascular manifestations of poisoning by the Indian Red Scorpion. Reduced insulin secretion in acute myocarditis produced by Buthus Tamulus venom injected in rabbits. Role of atropine in management of cardiovascular manifestations of scorpion envenoming in humans. Although majority of the exposures require minor or no treatment, there are situations where child may require admission in intensive care set-up. However, a sudden onset of organ dysfunction or clinical deterioration of a previously well child leads to a suspicion of poisoning. At times some toxic substance may cause specific type of symptom owing to their mechanism. This collective symptomatology is known as toxidromes, which may aid in diagnosing a particular class of poisoning. Witnesses and caretakers are asked about medication the child is taking, other medicines at home, empty or open containers of either medication or household products, and the surrounding in which the exposure occurred or child was found. Time elapsed since exposure is also very important to plan the treatment and may also alter the outcome.

A book of 63 chapters will always pose a challenge for its editors Every efort has been made in the preparation and editing of this and its publisher order generic cialis sublingual online. In this volume discount cialis sublingual 20mg with mastercard, we have heavily edited some indi- book to ensure that the details given (for instance of drug dosag- vidual contributions buy cialis sublingual 20 mg on-line, and worked assiduously in conjunction with es and pharmacokinetic values) are correct buy cialis sublingual now, but it is possible that the authors to avoid repetition or overlap. The reader is advised to refer to pub- permitted between chapters, this is because individual authors have lished information from the pharmaceutical companies and other taken difering (and occasionally conficting) approaches which reference works to check accuracy. We have also added editorial tables in places to ease comprehen- Simon Shorvon, for the editors sion and in particular to make the information contained in the London, 1996 Historical Introduction the Drug Treatment of Epilepsy from 1857 to 2015 Simon Shorvon In the historical introductions to the three previous editions of this has been because of an erroneous theoretical basis, an only modest book, therapeutic developments in three periods were covered, each impact on seizure control — if any impact at all — or the develop- from a diferent historical viewpoint: 1857–1939, 1938–1955, 1955– ment of sometimes serious side-efects, some of which took years 1989 [1,2,3]. It is not so much that the many adulatory claims further update (from 1989), judging this to be too close to garner an made for medicaments, now discarded, were deliberate deception, appropriate perspective. In its place, I have attempted to provide a but more that they refected the theoretical mores and fashions of timeline of antiepileptic drug therapy, listing pharmaceutical devel- the day. However, they do induce a sense of déjà vu — and should opments in mainstream clinical practice for the treatment of epilep- encourage a degree of skepticism when presented with assertions sy since 1857. A second timeline is also provided, in which surgical about contemporary therapies which are themselves based on an and other non-drug epilepsy therapies are listed, with events of im- equally transient state of knowledge. Both are accompanied by a commentary Secondly, the pace of new drug introductions varied considerably providing a brief contextual narrative. Tere has been a clear ‘concertina efect’ with bursts of snapshot of drug use at diferent times during this period is given activity followed by fallow periods. The purpose of this introductory chapter is to ofen been due, afer the discovery of a new class of drug, to the provide a synoptical overview of epilepsy therapeutics since 11 May development of close structural derivatives (‘me-too’ drugs; this 1857. This date was chosen as it was then that bromides, the frst happened for bromides, barbiturates, hydantoins, oxalozolidine modern therapy, were introduced into epilepsy practice, and as we diones, iminodibenzyls, pyrrolidones). Sometimes the derivatives pass the sesquicentennial of this momentous therapeutic advance, it have fared better than the parent drug, as has been the case with seems an appropriate topic to introduce this edition. Almost all the most signifcant advances in therapy ed on new technology, new models or new scientifc paradigms, have revolved around medicinal treatment. The introduc- has been devoted to surgical treatment, the number of patients re- tion of phenytoin thus depended on the new maximal electroshock ceiving surgery is still extremely small when compared with those model, the introduction of pregabalin, gabapentin, vigabatrin, ti- treated with drugs, and it remains a therapy largely of last resort. Pharmaceutical developments have dwarfed all others, physiology and biochemistry shows how science leads and com- and in relation to treatment and outcome most other clinical devel- mercialism follows, but the infuence of chance and of providence opment have been of marginal importance (it is striking how rela- can never be underestimated. Epilepsy therapeutics has never been tively little impact all the work on clinical description, classifcation entirely rationally based. Perhaps only Fourthly, the theoretical underpinning of drug introductions was developments in relation to the social aspects of epilepsy (reducing ofen also based on concepts of aetiology of epilepsy. In recent times, the concept that ilar have been the claims made for past and current drugs, even epilepsy is caused by a loss of the normal balance between excita- though these claims have ofen turned out to be overblown, and tion and inhibition, of specifc molecular or biochemical defects, how much therapy is dictated by fashion as much as science. Tese of reducing infammation or infuencing specifc genetic pathways facts alone emphasize the need for historical perspective, for with- are not altogether dissimilar. The relativism of our current scientifc out a knowledge of history the same mistakes made in the past are orthodoxies should not be underestimated, and current theories are inevitably repeated. Over these 150 or so years, a few general themes have emerged Finally, the social, commercial and political contexts have an which are worth enumeration. First, it is clear that most of the drugs enormous infuence, and this infuence is realized through such introduced over this period have not stood the test of time, despite processes as regulation and commercial practice. The current lack of new com- ance of sedatives, cool air, carotid compression, cold applications, pounds is partly due also to the increasing bureaucracy and regu- Galvanism, avoidance of ammonia and volatile stimulants and lation of recent years. He then considered the treatment of the premonito- transfer of drug discovery from the hospital or university setting, ry stage and chronic epilepsy and recommended ligatures to the typical in the frst half of the period, to the situation now where extremities, counter-irritation (e. The rise in treatment, purgatives, mineral tonics (‘heroic antiphlogistic treat- power and proftability of the pharmaceutical industry is one of the ments should be eschewed’), nitro-muriatic acid, gentian, decoc- striking features of the post-war therapeutic scene and of epilepsy tion of bark and sulphuric acid, olcum morrhuae (in other words, treatment. Sieveking remained skeptical about the indications are ofen larger and more proftable than epilepsy itself. This science of medicine, and, in its extremes, does more harm was the point made by Dr Edward Henry Sieveking, soon to become than any extra-professional quackery. In his paper, he dismissed specifc remedies and recommended He ended his long chapter on treatment by referring readers to the a more rounded approach with the use of counter-irritants, the pro- complete lists of therapies in the works of Tissot, Fraser, Cooke, Co- motion of healthy action of the secernent organs (secreting organs), pland and others, and by his now famous remark: and the toning up of the constitution by vegetable and metallic rob- In fact, there is not a substance in the material medica, there is orants (tonics). Delasiauve, in his book Traité de l’épilepsie of 1854, scarcely a substance in the world, capable of passing through made the same point, dividing therapy into: the gullet of man, that has not at one time or other enjoyed a 1 Debilitating therapies, such as bleeding, tepid baths; reputation of being an anti-epileptic. Despite the celebrated though, not for Sieveking’s paper — excellent though it pessimism of these leading doctors, it was nevertheless quite clear was – but for the remarks in the discussion that followed. In this, that bromide had changed the way physicians approached therapy the royal obstetrician Sir Charles Locock, chairman of the meet- in epilepsy. Tese drugs ushered in the modern age of antiepi- ing, reported his use of potassium bromide in hysterical catamenial leptics, with its emphasis on efcacy, side-efects, mechanism of epilepsy. Tus, on this rainy evening in London, the frst modern action and clinical therapeutics. This revolution started with bro- medical treatment for epilepsy, and the frst really efective ‘specifc’ mide in its formulation as a potassium salt, but was soon followed (or at least near-specifc), was launched. Tere were further reports by other formulations (notably as sodium, ammonium, strontium by Wilks, Radclife, Ramskill and Hughlings Jackson over the next or lithium salt, and by combination products) but no consensus few years, and by 1864 bromides had began to be very widely used. This was the start of In passing, it is interesting to note that at the meeting Locock also a trend for the production of ‘me-too’ drugs which has continued recommended removing over-crowded teeth and the cessation of to this day. In the same vein, Webster remarked afer Sieveking’s In this period, medicaments fell into three categories (Table 1): paper that onanism was a frequent cause of epilepsy especially in plant derivatives, animal derivatives and simple chemicals. Ter- southern climates, but Sieveking said he had not referred to the apy also was ofen divided into therapy for the acute seizures (or practice as ‘it was difcult to arrive at the truth in regard to this’, impending seizures) and chronic therapy. The plant and animal and that ‘he did not know how to proceed to determine it in the extracts were produced largely in local pharmacies and dispensa- case of females’. Tese were the birth pangs of the pharmaceutical in- which was a landmark in epilepsy therapeutics. His superb text Epilepsy tion of injury, counter-irritation by terebinthenate fomentations or and Other Chronic Convulsive Disorders [7] contained 50 pages on Historical Introduction xv Drug treatment for epilepsy Other treatments for epilepsy 1857 Sir Charles Locock reported the efectiveness of bromide 1854 Publication of Traité de l’épilepsie by Louis Delasiauve in hysterical catamenial epilepsy 1857 Publication of On Epilepsy and Epileptiform Seizures: Teir 1861 Samuel Wilks reported the efectiveness of bromide (com- Cases, Pathology and Treatment by E. He wrote in the second edition in 1901 that apart dance of light nourishment and tonics. This included the use of low salt di- The treatment of epilepsy is purely medicinal. It has always ets to reduce the requirement for bromide (so that the body would been so, but in a far more pronounced degree since the replace chloride with bromide; dechloridization), the use of com- almost accidental discovery, more than forty years ago, of bination therapies and the use of lower doses. With the advent of the infuence on the disease exerted by the combinations of bromides many previously widely used compounds fell from favour bromine. One adjunct though that did 1912–1988 impress him was borax, which Gowers himself frst introduced in In 1912, the hegemony of bromides was challenged for the frst his Goulstonian lecture of 1879, and this continued to have a place time by a totally new medicament. No been synthesized in 1904, and joined a group of barbiturates then new efective therapies were launched in the next 20 years and the being used as sedatives and hypnotics. Its antiepileptic properties transient nature of improvement on therapy was also recognized. The importance of this discovery was not initially Epileptics, are very readily infuenced by slight changes in widely recognized, partly because of its publication in an obscure the environment and in … treatment … [they] do well for a German language journal and also the greater medical priorities of time upon any change in treatment, whether that treatment the 1914–1918 war. It is have even seem improvement efected in a patient for months curious to see how opinion was divided about their relative merits, by mere change of locality. This was a text that defned advanced think- instance, could still write in the late 1930s in his standard neuro- ing of the time. In the book, he considered that only a few drugs logical textbook that: ‘although phenobarbital was at frst thought were of defnite beneft and his lists of efective and inefective drugs likely to supplant bromides as a remedy of choice’, it was ‘not its are shown in Table 3. He expounded in detail on the bromides, and of drugs vaunted at one time or another: all must stand the test of their various formulations, and also recommended their combina- experience, and … those which have successfully done so can be tion with opium or codein. This improved its therapeutic efectiveness and pheno- rgic sedative), serum therapy of Ceni and the coal tar derivatives barbital remains today one of the most prescribed medications for (antipyrin, phenacetin and acetanilide). In 1874, Bourneville, in his classic account of cy has never been shown to be signifcantly worse than any other status epilepticus, related the case of Marie Lamb who was treated at drug, and its fall in popularity in contemporary Western medicine the Salpêtrière with sinapisme (a topical remedy with a base of mus- is largely because of its side-efect profle, and its lack of marketing tard four), lavement purgative and quinine sulphate – to no efect. Other drugs used were apomorphine, hyoscine Intravenous phenobarbital was introduced in 1926 for status hydrobromate and chloroform. In 1903, Clark and Prout advocated epilepticus, and was sometimes mixed with chloroform, enemata chloroform, bromide and chloral.